5myb

From Proteopedia

(Difference between revisions)

Revision as of 17:53, 8 November 2023

Homodimerization of Tie2 Fibronectin-like domains 2 and 3 in space group P21

Structural highlights

5myb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TIE2_HUMAN Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:600195; an error of vascular morphogenesis characterized by dilated, serpiginous channels.^[1] ^[2] ^[3] ^[4] ^[5] Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.^[6] ^[7]

Function

TIE2_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17]

Publication Abstract from PubMed

The endothelial cell (EC)-specific receptor tyrosine kinases Tie1 and Tie2 are necessary for the remodeling and maturation of blood and lymphatic vessels. Angiopoietin-1 (Ang1) growth factor is a Tie2 agonist, whereas Ang2 functions as a context-dependent agonist/antagonist. The orphan receptor Tie1 modulates Tie2 activation, which is induced by association of angiopoietins with Tie2 in cis and across EC-EC junctions in trans Except for the binding of the C-terminal angiopoietin domains to the Tie2 ligand-binding domain, the mechanisms for Tie2 activation are poorly understood. We report here the structural basis of Ang1-induced Tie2 dimerization in cis and provide mechanistic insights on Ang2 antagonism, Tie1/Tie2 heterodimerization, and Tie2 clustering. We find that Ang1-induced Tie2 dimerization and activation occurs via the formation of an intermolecular beta-sheet between the membrane-proximal (third) Fibronectin type III domains (Fn3) of Tie2. The structures of Tie2 and Tie1 Fn3 domains are similar and compatible with Tie2/Tie1 heterodimerization by the same mechanism. Mutagenesis of the key interaction residues of Tie2 and Tie1 Fn3 domains decreased Ang1-induced Tie2 phosphorylation and increased the basal phosphorylation of Tie1, respectively. Furthermore, the Tie2 structures revealed additional interactions between the Fn 2 (Fn2) domains that coincide with a mutation of Tie2 in primary congenital glaucoma that leads to defective Tie2 clustering and junctional localization. Mutagenesis of the Fn2-Fn2 interface increased the basal phosphorylation of Tie2, suggesting that the Fn2 interactions are essential in preformed Tie2 oligomerization. The interactions of the membrane-proximal domains could provide new targets for modulation of Tie receptor activity.

Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization.,Leppanen VM, Saharinen P, Alitalo K Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4376-4381. doi:, 10.1073/pnas.1616166114. Epub 2017 Apr 10. PMID:28396439^[18]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
↑ Vikkula M, Boon LM, Carraway KL 3rd, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996 Dec 27;87(7):1181-90. PMID:8980225
↑ Calvert JT, Riney TJ, Kontos CD, Cha EH, Prieto VG, Shea CR, Berg JN, Nevin NC, Simpson SA, Pasyk KA, Speer MC, Peters KG, Marchuk DA. Allelic and locus heterogeneity in inherited venous malformations. Hum Mol Genet. 1999 Jul;8(7):1279-89. PMID:10369874
↑ Wouters V, Limaye N, Uebelhoer M, Irrthum A, Boon LM, Mulliken JB, Enjolras O, Baselga E, Berg J, Dompmartin A, Ivarsson SA, Kangesu L, Lacassie Y, Murphy J, Teebi AS, Penington A, Rieu P, Vikkula M. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur J Hum Genet. 2010 Apr;18(4):414-20. doi: 10.1038/ejhg.2009.193. Epub 2009 Nov, 4. PMID:19888299 doi:10.1038/ejhg.2009.193
↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
↑ Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997 Jul 4;277(5322):55-60. PMID:9204896
↑ Cascone I, Audero E, Giraudo E, Napione L, Maniero F, Philips MR, Collard JG, Serini G, Bussolino F. Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1. Blood. 2003 Oct 1;102(7):2482-90. Epub 2003 Jun 19. PMID:12816861 doi:10.1182/blood-2003-03-0670
↑ Lee HJ, Cho CH, Hwang SJ, Choi HH, Kim KT, Ahn SY, Kim JH, Oh JL, Lee GM, Koh GY. Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J. 2004 Aug;18(11):1200-8. PMID:15284220 doi:10.1096/fj.03-1466com
↑ Audero E, Cascone I, Maniero F, Napione L, Arese M, Lanfrancone L, Bussolino F. Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. J Biol Chem. 2004 Mar 26;279(13):13224-33. Epub 2003 Dec 9. PMID:14665640 doi:10.1074/jbc.M307456200
↑ Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol. 2005 Apr 25;169(2):239-43. PMID:15851516 doi:10.1083/jcb.200411105
↑ Fukuhara S, Sako K, Minami T, Noda K, Kim HZ, Kodama T, Shibuya M, Takakura N, Koh GY, Mochizuki N. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol. 2008 May;10(5):513-26. doi: 10.1038/ncb1714. Epub 2008 Apr 20. PMID:18425120 doi:10.1038/ncb1714
↑ Saharinen P, Eklund L, Miettinen J, Wirkkala R, Anisimov A, Winderlich M, Nottebaum A, Vestweber D, Deutsch U, Koh GY, Olsen BR, Alitalo K. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008 May;10(5):527-37. doi: 10.1038/ncb1715. Epub 2008 Apr 20. PMID:18425119 doi:10.1038/ncb1715
↑ Yuan HT, Khankin EV, Karumanchi SA, Parikh SM. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009 Apr;29(8):2011-22. doi: 10.1128/MCB.01472-08. Epub 2009 Feb, 17. PMID:19223473 doi:10.1128/MCB.01472-08
↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
↑ Leppanen VM, Saharinen P, Alitalo K. Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization. Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4376-4381. doi:, 10.1073/pnas.1616166114. Epub 2017 Apr 10. PMID:28396439 doi:http://dx.doi.org/10.1073/pnas.1616166114

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5myb"

Categories: Homo sapiens | Large Structures | Alitalo K | Leppanen V-M | Saharinen P

@@ Line 3: / Line 3: @@
 <StructureSection load='5myb' size='340' side='right'caption='[[5myb]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5myb]] is a 2 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=5MYB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MYB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5myb]] is a 2 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=5MYB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MYB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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]] 2.6&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TEK, TIE2, VMCM, VMCM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=5myb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5myb OCA], [https://pdbe.org/5myb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5myb RCSB], [https://www.ebi.ac.uk/pdbsum/5myb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5myb ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5myb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5myb OCA], [http://pdbe.org/5myb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5myb RCSB], [http://www.ebi.ac.uk/pdbsum/5myb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5myb ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN]] Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:[http://omim.org/entry/600195 600195]]; an error of vascular morphogenesis characterized by dilated, serpiginous channels.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> <ref>PMID:8980225</ref> <ref>PMID:10369874</ref> <ref>PMID:19888299</ref>   Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
+[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:[https://omim.org/entry/600195 600195]; an error of vascular morphogenesis characterized by dilated, serpiginous channels.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> <ref>PMID:8980225</ref> <ref>PMID:10369874</ref> <ref>PMID:19888299</ref>   Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.<ref>PMID:9204896</ref> <ref>PMID:12816861</ref> <ref>PMID:15284220</ref> <ref>PMID:14665640</ref> <ref>PMID:15851516</ref> <ref>PMID:18425120</ref> <ref>PMID:18425119</ref> <ref>PMID:19223473</ref> <ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
+[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.<ref>PMID:9204896</ref> <ref>PMID:12816861</ref> <ref>PMID:15284220</ref> <ref>PMID:14665640</ref> <ref>PMID:15851516</ref> <ref>PMID:18425120</ref> <ref>PMID:18425119</ref> <ref>PMID:19223473</ref> <ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Receptor protein-tyrosine kinase]]
+[[Category: Alitalo K]]
-[[Category: Alitalo, K]]
+[[Category: Leppanen V-M]]
-[[Category: Leppanen, V M]]
+[[Category: Saharinen P]]
-[[Category: Saharinen, P]]
-[[Category: Dimerization]]
-[[Category: Fibronectin-like domain]]
-[[Category: Homotypic interaction]]
-[[Category: Receptor]]
-[[Category: Signaling protein]]

5myb

From Proteopedia

Revision as of 17:53, 8 November 2023

Homodimerization of Tie2 Fibronectin-like domains 2 and 3 in space group P21

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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