2iim

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'''SH3 Domain of Human Lck'''<br />
'''SH3 Domain of Human Lck'''<br />
==Overview==
==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.
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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.
==Disease==
==Disease==
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==About this Structure==
==About this Structure==
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2IIM is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, CA and PG4 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2IIM OCA].
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2IIM is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=PG4:'>PG4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IIM OCA].
==Reference==
==Reference==
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[[Category: Single protein]]
[[Category: Single protein]]
[[Category: Egerer-Sieber, C.]]
[[Category: Egerer-Sieber, C.]]
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[[Category: Muller, Y.A.]]
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[[Category: Muller, Y A.]]
[[Category: Romir, J.]]
[[Category: Romir, J.]]
[[Category: CA]]
[[Category: CA]]
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[[Category: beta-barrels]]
[[Category: beta-barrels]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:44:48 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:53:06 2008''

Revision as of 15:53, 21 February 2008

Image:2iim.gif

2iim, resolution 1.0Å

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SH3 Domain of Human Lck

Contents

Overview

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.

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 with , and as ligands. 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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