2iim
|
SH3 Domain of Human Lck
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
About this StructureAbout this Structure
2IIM is a Single protein structure of sequence from Homo sapiens with ZN, CA and PG4 as ligands. Full crystallographic information is available from OCA.
ReferenceReference
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
Page seeded by OCA on Mon Nov 12 22:44:48 2007