1x27: Difference between revisions
New page: left|200px<br /> <applet load="1x27" size="450" color="white" frame="true" align="right" spinBox="true" caption="1x27, resolution 2.7Å" /> '''Crystal Structure of... |
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[[Image:1x27.gif|left|200px]]<br /> | [[Image:1x27.gif|left|200px]]<br /><applet load="1x27" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1x27, resolution 2.7Å" /> | caption="1x27, resolution 2.7Å" /> | ||
'''Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas'''<br /> | '''Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas'''<br /> | ||
==Overview== | ==Overview== | ||
The docking protein p130Cas (Cas) becomes tyrosine-phosphorylated in its | 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. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1X27 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NA as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | 1X27 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NA:'>NA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X27 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Transferase]] | [[Category: Transferase]] | ||
[[Category: Becherer, K.]] | [[Category: Becherer, K.]] | ||
[[Category: Ely, K | [[Category: Ely, K R.]] | ||
[[Category: Kodandapani, R.]] | [[Category: Kodandapani, R.]] | ||
[[Category: Liljas, L.]] | [[Category: Liljas, L.]] | ||
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[[Category: lck-cas complex]] | [[Category: lck-cas complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:50:19 2008'' | ||
Revision as of 16:50, 21 February 2008
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Crystal Structure of Lck SH2-SH3 with SH2 binding site of p130Cas
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
About this StructureAbout this Structure
1X27 is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
ReferenceReference
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
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