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1x27

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Revision as of 09:34, 6 January 2021

Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas

Structural highlights

1x27 is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Related:	1lck
Gene:	LCK (HUMAN)
Activity:	Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[LCK_HUMAN] Severe combined immunodeficiency due to LCK deficiency. Note=A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB. [BCAR1_RAT] Appears to have a central function in transformation of some cell types.

Function

[LCK_HUMAN] Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] [BCAR1_RAT] Docking protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion. Implicated in induction of cell migration (By similarity).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The docking protein p130Cas (Cas) becomes tyrosine-phosphorylated in its central substrate domain in response to extracellular stimuli such as integrin-mediated cell adhesion, and transmits signals through interactions with various intracellular signaling molecules such as the adaptor protein Crk. Src-family kinases (SFKs) bind a specific site in the carboxyl-terminal region of Cas and subsequently SFKs phosphorylate progressively the substrate domain in Cas. In this study crystallography, mutagenesis and binding assays were used to understand the molecular basis for Cas interactions with SFKs. Tyrosine phosphorylation regulates binding of Cas to SFKs, and the primary site for this phosphorylation, Y762, has been proposed. A phosphorylated peptide corresponding to Cas residues 759MEDpYDYVHL767 containing the key phosphotyrosine was crystallized in complex with the SH3-SH2 domain of the SFK Lck. The results provide the first structural data for this protein-protein interaction. The motif in Cas 762pYDYV binds to the SH2 domain in a mode that mimics high-affinity ligands, involving dual contacts of Y762 and V765 with conserved residues in SFK SH2 domains. In addition, Y764 is in position to make an electrostatic contact after phosphorylation with a conserved SFK arginine that mediates interactions with other high-affinity SH2 binders. These new molecular data suggest that Cas may regulate activity of Src as a competing ligand to displace intramolecular interactions that occur in SFKs (between the C-terminal tail and the SH2 domain) and restrain and down-regulate the kinase in an inactive form.

Molecular basis for regulation of Src by the docking protein p130Cas.,Nasertorabi F, Tars K, Becherer K, Kodandapani R, Liljas L, Vuori K, Ely KR J Mol Recognit. 2006 Jan-Feb;19(1):30-8. PMID:16245368^[7]

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

References

↑ Gelkop S, Gish GD, Babichev Y, Pawson T, Isakov N. T cell activation-induced CrkII binding to the Zap70 protein tyrosine kinase is mediated by Lck-dependent phosphorylation of Zap70 tyrosine 315. J Immunol. 2005 Dec 15;175(12):8123-32. PMID:16339550
↑ Mason LH, Willette-Brown J, Taylor LS, McVicar DW. Regulation of Ly49D/DAP12 signal transduction by Src-family kinases and CD45. J Immunol. 2006 Jun 1;176(11):6615-23. PMID:16709819
↑ Goh YM, Cinghu S, Hong ET, Lee YS, Kim JH, Jang JW, Li YH, Chi XZ, Lee KS, Wee H, Ito Y, Oh BC, Bae SC. Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the cytoplasm. J Biol Chem. 2010 Mar 26;285(13):10122-9. doi: 10.1074/jbc.M109.071381. Epub 2010, Jan 25. PMID:20100835 doi:10.1074/jbc.M109.071381
↑ Collins M, Tremblay M, Chapman N, Curtiss M, Rothman PB, Houtman JC. The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol. 2009 Dec 22. PMID:20028775 doi:jlb.0409227
↑ Wang H, Zeng X, Fan Z, Lim B. RhoH modulates pre-TCR and TCR signalling by regulating LCK. Cell Signal. 2011 Jan;23(1):249-58. doi: 10.1016/j.cellsig.2010.09.009. Epub 2010, Sep 16. PMID:20851766 doi:10.1016/j.cellsig.2010.09.009
↑ Scales TM, Derkinderen P, Leung KY, Byers HL, Ward MA, Price C, Bird IN, Perera T, Kellie S, Williamson R, Anderton BH, Reynolds CH. Tyrosine phosphorylation of tau by the SRC family kinases lck and fyn. Mol Neurodegener. 2011 Jan 26;6:12. doi: 10.1186/1750-1326-6-12. PMID:21269457 doi:10.1186/1750-1326-6-12
↑ Nasertorabi F, Tars K, Becherer K, Kodandapani R, Liljas L, Vuori K, Ely KR. Molecular basis for regulation of Src by the docking protein p130Cas. J Mol Recognit. 2006 Jan-Feb;19(1):30-8. PMID:16245368 doi:10.1002/jmr.755

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1x27"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas==
-<StructureSection load='1x27' size='340' side='right' caption='[[1x27]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+<StructureSection load='1x27' size='340' side='right'caption='[[1x27]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1x27]] is a 12 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=1X27 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1X27 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1x27]] is a 12 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=1X27 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1X27 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1lck|1lck]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1lck|1lck]]</div></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LCK ([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='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=1x27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x27 OCA], [http://pdbe.org/1x27 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1x27 RCSB], [http://www.ebi.ac.uk/pdbsum/1x27 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1x27 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=1x27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x27 OCA], [http://pdbe.org/1x27 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1x27 RCSB], [http://www.ebi.ac.uk/pdbsum/1x27 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1x27 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 36: / Line 36: @@
 ==See Also==
-*[[Tyrosine kinase|Tyrosine kinase]]
+*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
 == References ==
 <references/>
@@ Line 42: / Line 42: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Transferase]]
 [[Category: Becherer, K]]

1x27

From Proteopedia

Revision as of 09:34, 6 January 2021

Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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