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Proline-Rich Sequences that Bind to Src Homology 3 Domains with Individual Specificities

Alexandropoulos, Konstantina and Cheng, Genhong and Baltimore, David (1995) Proline-Rich Sequences that Bind to Src Homology 3 Domains with Individual Specificities. Proceedings of the National Academy of Sciences of the United States of America, 92 (8). pp. 3110-3114. ISSN 0027-8424. PMCID PMC42114. doi:10.1073/pnas.92.8.3110.

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To study the binding specificity of Src homology 3 (SH3) domains, we have screened a mouse embryonic expression library for peptide fragments that interact with them. Several clones were identified that express fragments of proteins which, through proline-rich binding sites, exhibit differential binding specificity to various SH3 domains. Src-SH3-specific binding uses a sequence of 7 aa of the consensus RPLPXXP, in which the N-terminal arginine is very important. The SH3 domains of the Src-related kinases Fyn, Lyn, and Hck bind to this sequence with the same affinity as that of the Src SH3. In contrast, a quite different proline-rich sequence from the Btk protein kinase binds to the Fyn, Lyn, and Hck SH3 domains, but not to the Src SH3. Specific binding of the Abl SH3 requires a longer, more proline-rich sequence but no arginine. One clone that binds to both Src and Abl SH3 domains through a common site exhibits reversed binding orientation, in that an arginine indispensable for binding to all tested SH3 domains occurs at the C terminus. Another clone contains overlapping yet distinct Src and Abl SH3 binding sites. Binding to the SH3 domains is mediated by a common PXXP amino acid sequence motif present on all ligands, and specificity comes about from other interactions, often ones involving arginine. The rules governing in vivo usage of particular sites by particular SH3 domains are not clear, but one binding orientation may be more specific than another.

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URLURL TypeDescription CentralArticle
Baltimore, David0000-0001-8723-8190
Additional Information:© 1995 by National Academy of Sciences Contributed by David Baltimore, January 3, 1995. We thank Drs. Bruce Mayer, Christopher Roman, Ruibao Ren, and George Cohen for critically reading the manuscript. K.A. was supported by National Institutes of Health Grant 7F32 CA60458-02. G.C. is the recipient of an Irvington House Institute fellowship. This work was supported by National Institutes of Health Grant 7R01 CA51462-07 to D.B. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
NIH Postdoctoral Fellowship7F32 CA60458-02
Irvington Institute for Medical ResearchUNSPECIFIED
NIH7R01 CA51462-07
Subject Keywords:Abl, Src, protein-tyrosine kinase, protein-protein interaction
Issue or Number:8
PubMed Central ID:PMC42114
Record Number:CaltechAUTHORS:ALEpnas95
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Official Citation:Proline-rich sequences that bind to Src homology 3 domains with individual specificities. K Alexandropoulos, G Cheng, D Baltimore Proceedings of the National Academy of Sciences Apr 1995, 92 (8) 3110-3114; DOI: 10.1073/pnas.92.8.3110
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:692
Deposited By: Archive Administrator
Deposited On:14 Sep 2005
Last Modified:08 Nov 2021 19:04

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