2abl - Revision history

OCA at 09:12, 14 February 2024

2024-02-14T09:12:22Z

←Older revision		Revision as of 09:12, 14 February 2024
Line 3:		Line 3:
	<StructureSection load='2abl' size='340' side='right'caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>		<StructureSection load='2abl' size='340' side='right'caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ABL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ABL FirstGlance]. <br>
-	</td></tr><tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>ABL SH3-SH2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=9606 HUMAN])</td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.5Å</td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~">~~<b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>~~[~~https://en.wikipedia.org/wiki/Transferase Transferase~~]~~, with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=~~2.~~7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span>~~</td></tr>	+
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [https://pdbe.org/2abl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [https://www.ebi.ac.uk/pdbsum/2abl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2abl ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [https://pdbe.org/2abl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [https://www.ebi.ac.uk/pdbsum/2abl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2abl ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).	+	[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>	+	[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
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	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2abl ConSurf].		</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2abl ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	BACKGROUND. The Abl nonreceptor tyrosine kinase is implicated in a range of cellular processes and its transforming variants are involved in human leukemias. The N-terminal regulatory region of the Abl protein contains Src homology domains SH2 and SH3 which have been shown to be important for the regulation of its activity in vivo. These domains are often found together in the same protein and biochemical data suggest that the functions of one domain can be influenced by the other. RESULTS. We have determined the crystal structure of the Abl regulatory region containing the SH3 and SH2 domains. In general, the individual domains are very similar to those of previously solved structures, although the Abl SH2 domain contains a loop which is extended so that one side of the resulting phosphotyrosine-binding pocket is open. In our structure the protein exists as a monomer with no intermolecular contacts to which a biological function may be attributed. However, there is a significant intramolecular contact between a loop of the SH3 domain and the extended loop of the SH2 domain. This contact surface includes the SH2 loop segment that is responsible for binding the phosphate moiety of phosphotyrosine-containing proteins and is therefore critical for orienting peptide interactions. CONCLUSIONS. The crystal structure of the composite Abl SH3-SH2 domain provides the first indication of how SH2 and SH3 domains communicate with each other within the same molecule and why the presence of one directly influences the activity of the other. This is the first clear evidence that these two domains are in contact with each other. The results suggest that this direct interaction between the two domains may affect the ligand binding properties of the SH2 domain, thus providing an explanation for biochemical and functional data concerning the Bcr-Abl kinase.
-
-	Intramolecular interactions of the regulatory domains of the Bcr-Abl kinase reveal a novel control mechanism.,Nam HJ, Haser WG, Roberts TM, Frederick CA Structure. 1996 Sep 15;4(9):1105-14. PMID:8805596<ref>PMID:8805596</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 2abl" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Transferase]]~~	+	[[Category: Frederick CA]]
-	[[Category: Frederick~~, C A~~]]	+	[[Category: Nam H-J]]
-	[[Category: Nam, H J]]	+
-	~~[[Category: Oncoprotein]]~~	+
-	~~[[Category: Sh2]]~~	+
-	~~[[Category: Sh3]]~~	+
-	~~[[Category: Tyrosine kinase~~]]	+

OCA at 08:29, 27 January 2021

2021-01-27T08:29:18Z

←Older revision		Revision as of 08:29, 27 January 2021
Line 1:		Line 1:

	==SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE==		==SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE==
-	<StructureSection load='2abl' size='340' side='right' caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>	+	<StructureSection load='2abl' size='340' side='right'caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2ABL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ABL FirstGlance]. <br>
-	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/Transferase Transferase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Transferase Transferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [~~http~~://pdbe.org/2abl PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/2abl PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=2abl ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [https://pdbe.org/2abl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [https://www.ebi.ac.uk/pdbsum/2abl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2abl ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).	+	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>	+	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
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	==See Also==		==See Also==
-	*[[Tyrosine kinase\|Tyrosine kinase]]	+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
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	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Frederick, C A]]		[[Category: Frederick, C A]]

OCA at 07:29, 9 May 2018

2018-05-09T07:29:40Z

←Older revision		Revision as of 07:29, 9 May 2018
Line 1:		Line 1:
		+
	==SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE==		==SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE==
	<StructureSection load='2abl' size='340' side='right' caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>		<StructureSection load='2abl' size='340' side='right' caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [http://pdbe.org/2abl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [http://www.ebi.ac.uk/pdbsum/2abl PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [http://pdbe.org/2abl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [http://www.ebi.ac.uk/pdbsum/2abl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2abl ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 15:		Line 16:
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ab/2abl_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ab/2abl_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>

OCA at 19:21, 8 February 2016

2016-02-08T19:21:03Z

←Older revision		Revision as of 19:21, 8 February 2016
Line 19:		Line 19:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2abl ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">

OCA at 14:37, 10 September 2015

2015-09-10T14:37:53Z

←Older revision		Revision as of 14:37, 10 September 2015
Line 2:		Line 2:
	<StructureSection load='2abl' size='340' side='right' caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>		<StructureSection load='2abl' size='340' side='right' caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ABL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ABL FirstGlance]. <br>
-	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [http://www.ebi.ac.uk/pdbsum/2abl PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [http://pdbe.org/2abl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [http://www.ebi.ac.uk/pdbsum/2abl PDBsum]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 29:		Line 29:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 2abl" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 36:		Line 37:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Frederick, C A]]		[[Category: Frederick, C A]]

OCA at 10:46, 8 January 2015

2015-01-08T10:46:52Z

←Older revision		Revision as of 10:46, 8 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ABL FirstGlance]. <br>		<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ABL FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>	+	</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [http://www.ebi.ac.uk/pdbsum/2abl PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [http://www.ebi.ac.uk/pdbsum/2abl PDBsum]</span></td></tr>
-	<table>	+	</table>
	== Disease ==		== Disease ==
	[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).		[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
Line 38:		Line 38:
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Transferase]]		[[Category: Transferase]]
-	[[Category: Frederick, C A.]]	+	[[Category: Frederick, C A]]
-	[[Category: Nam, H J.]]	+	[[Category: Nam, H J]]
	[[Category: Oncoprotein]]		[[Category: Oncoprotein]]
	[[Category: Sh2]]		[[Category: Sh2]]
	[[Category: Sh3]]		[[Category: Sh3]]
-	[[Category: Transferase]]
	[[Category: Tyrosine kinase]]		[[Category: Tyrosine kinase]]

OCA at 01:28, 30 September 2014

2014-09-30T01:28:56Z

←Older revision		Revision as of 01:28, 30 September 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_2abl\| PDB=2abl \| SCENE= }}~~	+	==SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE==
-	===SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE===	+	<StructureSection load='2abl' size='340' side='right' caption='[[2abl]], [[Resolution\|resolution]] 2.50Å' scene=''>
-	~~{{ABSTRACT_PUBMED_8805596}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[2abl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ABL FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL SH3-SH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
		+	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2abl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2abl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2abl RCSB], [http://www.ebi.ac.uk/pdbsum/2abl PDBsum]</span></td></tr>
		+	<table>
		+	== Disease ==
	[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).		[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ab/2abl_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	BACKGROUND. The Abl nonreceptor tyrosine kinase is implicated in a range of cellular processes and its transforming variants are involved in human leukemias. The N-terminal regulatory region of the Abl protein contains Src homology domains SH2 and SH3 which have been shown to be important for the regulation of its activity in vivo. These domains are often found together in the same protein and biochemical data suggest that the functions of one domain can be influenced by the other. RESULTS. We have determined the crystal structure of the Abl regulatory region containing the SH3 and SH2 domains. In general, the individual domains are very similar to those of previously solved structures, although the Abl SH2 domain contains a loop which is extended so that one side of the resulting phosphotyrosine-binding pocket is open. In our structure the protein exists as a monomer with no intermolecular contacts to which a biological function may be attributed. However, there is a significant intramolecular contact between a loop of the SH3 domain and the extended loop of the SH2 domain. This contact surface includes the SH2 loop segment that is responsible for binding the phosphate moiety of phosphotyrosine-containing proteins and is therefore critical for orienting peptide interactions. CONCLUSIONS. The crystal structure of the composite Abl SH3-SH2 domain provides the first indication of how SH2 and SH3 domains communicate with each other within the same molecule and why the presence of one directly influences the activity of the other. This is the first clear evidence that these two domains are in contact with each other. The results suggest that this direct interaction between the two domains may affect the ligand binding properties of the SH2 domain, thus providing an explanation for biochemical and functional data concerning the Bcr-Abl kinase.

-	~~==Function==~~	+	Intramolecular interactions of the regulatory domains of the Bcr-Abl kinase reveal a novel control mechanism.,Nam HJ, Haser WG, Roberts TM, Frederick CA Structure. 1996 Sep 15;4(9):1105-14. PMID:8805596<ref>PMID:8805596</ref>
-	[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of ~~WASF3 is critical for~~ the ~~stimulation~~ of ~~lamellipodia formation and cell migration. Involved in~~ the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-~~mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes~~. ~~Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover~~, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, ~~DDB2~~, ~~ERCC3~~, ~~ERCC6, RAD9A, RAD51, RAD52 or WRN~~. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (~~translocated intimin receptor~~) ~~of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin~~-~~associated gene A) of H~~.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref><ref>PMID:9144171</ref><ref>PMID:9461559</ref><ref>PMID:10391250</ref><ref>PMID:12379650</ref><ref>PMID:11971963</ref><ref>PMID:12531427</ref><ref>PMID:12672821</ref><ref>PMID:15556646</ref><ref>PMID:15031292</ref><ref>PMID:15886098</ref><ref>PMID:15657060</ref><ref>PMID:16943190</ref><ref>PMID:16678104</ref><ref>PMID:17306540</ref><ref>PMID:17623672</ref><ref>PMID:18328268</ref><ref>PMID:18945674</ref><ref>PMID:19891780</ref><ref>PMID:20417104</ref><ref>PMID:16424036</ref><ref>PMID:~~20357770~~</ref>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[2abl]] is~~ a ~~1 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA].~~	+	</div>

	==See Also==		==See Also==
	*[[Tyrosine kinase\|Tyrosine kinase]]		*[[Tyrosine kinase\|Tyrosine kinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:008805596</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 20:23, 24 March 2013

2013-03-24T20:23:06Z

←Older revision		Revision as of 20:23, 24 March 2013
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-	[[Image:2abl.png\|left\|200px]]
-
	{{STRUCTURE_2abl\| PDB=2abl \| SCENE= }}		{{STRUCTURE_2abl\| PDB=2abl \| SCENE= }}
-
	===SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE===		===SH3-SH2 DOMAIN FRAGMENT OF HUMAN BCR-ABL TYROSINE KINASE===
		+	{{ABSTRACT_PUBMED_8805596}}

-	~~{{ABSTRACT_PUBMED_8805596}}~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref><ref>PMID:9144171</ref><ref>PMID:9461559</ref><ref>PMID:10391250</ref><ref>PMID:12379650</ref><ref>PMID:11971963</ref><ref>PMID:12531427</ref><ref>PMID:12672821</ref><ref>PMID:15556646</ref><ref>PMID:15031292</ref><ref>PMID:15886098</ref><ref>PMID:15657060</ref><ref>PMID:16943190</ref><ref>PMID:16678104</ref><ref>PMID:17306540</ref><ref>PMID:17623672</ref><ref>PMID:18328268</ref><ref>PMID:18945674</ref><ref>PMID:19891780</ref><ref>PMID:20417104</ref><ref>PMID:16424036</ref><ref>PMID:20357770</ref>

	==About this Structure==		==About this Structure==
Line 14:		Line 16:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:008805596</ref><references group="xtra"/>	+	<ref group="xtra">PMID:008805596</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 11:12, 20 October 2012

2012-10-20T11:12:39Z

←Older revision		Revision as of 11:12, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[2abl]] is a 1 chain structure ~~of [[Tyrosine kinase]]~~ with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA].	+	[[2abl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ABL OCA].

	==See Also==		==See Also==

OCA: Protected "2abl" [edit=sysop:move=sysop]

2012-07-26T04:35:58Z

Protected "2abl" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:35, 26 July 2012