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| - | [[Image:2iim.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2iim| PDB=2iim | SCENE= }} | | {{STRUCTURE_2iim| PDB=2iim | SCENE= }} |
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| - | '''SH3 Domain of Human Lck'''
| + | ===SH3 Domain of Human Lck=== |
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| - | ==Overview==
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| - | In cytosolic Src-type tyrosine kinases the Src-type homology 3 (SH3) domain binds to an internal proline-rich motif and the presence or the absence of this interaction modulates the kinase enzymatic activity. The Src-type kinase Lck plays an important role during T-cell activation and development, since it phosphorylates the T-cell antigen receptor in an early step of the activation pathway. We have determined the crystal structure of the SH3 domain from Lck kinase at a near-atomic resolution of 1.0 A. Unexpectedly, the Lck-SH3 domain forms a symmetrical homodimer in the crystal and the dimer comprises two identical zinc-binding sites in the interface. The atomic interactions formed across the dimer interface resemble strikingly those observed between SH3 domains and their canonical proline-rich ligands, since almost identical residues participate in both contacts. Ultracentrifugation experiments confirm that in the presence of zinc ions, the Lck-SH3 domain also forms dimers in solution. The Zn(2+) dissociation constant from the Lck-SH3 dimer is estimated to be lower than 100 nM. Moreover, upon addition of a proline-rich peptide with a sequence corresponding to the recognition segment of the herpesviral regulatory protein Tip, competition between zinc-induced homodimerization and binding of the peptide can be detected by both fluorescence spectroscopy and analytical ultracentrifugation. These results suggest that in vivo, too, competition between Lck-SH3 homodimerization and binding of regulatory proline-rich sequence motifs possibly represents a novel mechanism by which kinase activity is modulated. Because the residues that form the zinc-binding site are highly conserved among Lck orthologues but not in other Src-type kinases, the mechanism might be peculiar to Lck and to its role in the initial steps of T-cell activation.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_17118402}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 17118402 is the PubMed ID number. |
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| | ==Disease== | | ==Disease== |
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| | [[Category: Romir, J.]] | | [[Category: Romir, J.]] |
| | [[Category: Beta-barrel]] | | [[Category: Beta-barrel]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:32:58 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 15:07:57 2008'' |
Revision as of 12:08, 28 July 2008
Template:STRUCTURE 2iim
SH3 Domain of Human Lck
Template:ABSTRACT PUBMED 17118402
Disease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
About this Structure
2IIM is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structure analysis and solution studies of human Lck-SH3; zinc-induced homodimerization competes with the binding of proline-rich motifs., Romir J, Lilie H, Egerer-Sieber C, Bauer F, Sticht H, Muller YA, J Mol Biol. 2007 Feb 2;365(5):1417-28. Epub 2006 Oct 21. PMID:17118402
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