HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: M700312-MCP200v1 7/4/768    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Glossary Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, H. Articles by Li, S. S.-C. Search for Related Content PubMed PubMed Citation Articles by Huang, H. Articles by Li, S. S.-C. Social Bookmarking                      What's this?

Molecular & Cellular Proteomics 7:768-784, 2008.
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

---

Research

Defining the Specificity Space of the Human Src Homology 2 Domain^*,S

Haiming Huang^,, Lei Li^,, Chenggang Wu^,, David Schibli, Karen Colwill^¶, Sucan Ma^||, Chengjun Li, Protiva Roy, Krystina Ho, Zhou Songyang^**, Tony Pawson^¶, Youhe Gao^|| and Shawn S.-C. Li^,

From the Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada, ^¶ Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto M5G 1X8, Canada, ^|| Proteomics Research Center, National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/Peking Union Medical College, 100005 Beijing, China, and ^** Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030

Src homology 2 (SH2) domains are the largest family of interaction modules encoded by the human genome to recognize tyrosine-phosphorylated sequences and thereby play pivotal roles in transducing and controlling cellular signals emanating from protein-tyrosine kinases. Different SH2 domains select for distinct phosphopeptides, and the function of a given SH2 domain is often dictated by the specific motifs that it recognizes. Therefore, deciphering the phosphotyrosyl peptide motif recognized by an SH2 domain is the key to understanding its cellular function. Here we cloned all 120 SH2 domains identified in the human genome and determined the phosphotyrosyl peptide binding properties of 76 SH2 domains by screening an oriented peptide array library. Of these 76, we defined the selectivity for 43 SH2 domains and refined the binding motifs for another 33 SH2 domains. We identified a number of novel binding motifs, which are exemplified by the BRDG1 SH2 domain that selects specifically for a bulky, hydrophobic residue at P + 4 relative to the Tyr(P) residue. Based on the oriented peptide array library data, we developed scoring matrix-assisted ligand identification (or SMALI), a Web-based program for predicting binding partners for SH2-containing proteins. When applied to SH2D1A/SAP (SLAM-associated protein), a protein whose mutation or deletion underlies the X-linked lymphoproliferative syndrome, SMALI not only recapitulated known interactions but also identified a number of novel interacting proteins for this disease-associated protein. SMALI also identified a number of potential interactors for BRDG1, a protein whose function is largely unknown. Peptide in-solution binding analysis demonstrated that a SMALI score correlates well with the binding energy of a peptide to a given SH2 domain. The definition of the specificity space of the human SH2 domain provides both the necessary molecular basis and a platform for future exploration of the functions for SH2-containing proteins in cells.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Sulahian, O. Cleaver, and L. J.-s. Huang Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia Blood, May 21, 2009; 113(21): 5287 - 5297. [Abstract] [Full Text] [PDF]

				M.-E. Huot, C. M. Brown, N. Lamarche-Vane, and S. Richard An Adaptor Role for Cytoplasmic Sam68 in Modulating Src Activity during Cell Polarization Mol. Cell. Biol., April 1, 2009; 29(7): 1933 - 1943. [Abstract] [Full Text] [PDF]

				S. Hanke and M. Mann The Phosphotyrosine Interactome of the Insulin Receptor Family and Its Substrates IRS-1 and IRS-2 Mol. Cell. Proteomics, March 1, 2009; 8(3): 519 - 534. [Abstract] [Full Text] [PDF]

				V. A. McPherson, S. Everingham, R. Karisch, J. A. Smith, C. M. Udell, J. Zheng, Z. Jia, and A. W. B. Craig Contributions of F-BAR and SH2 Domains of Fes Protein Tyrosine Kinase for Coupling to the Fc{varepsilon}RI Pathway in Mast Cells Mol. Cell. Biol., January 15, 2009; 29(2): 389 - 401. [Abstract] [Full Text] [PDF]

				A. Zoubeidi, J. Rocha, F. Z. Zouanat, L. Hamel, E. Scarlata, A. G. Aprikian, and S. Chevalier The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth Mol. Cancer Res., January 1, 2009; 7(1): 142 - 155. [Abstract] [Full Text] [PDF]

				M. L. Miller, L. J. Jensen, F. Diella, C. Jorgensen, M. Tinti, L. Li, M. Hsiung, S. A. Parker, J. Bordeaux, T. Sicheritz-Ponten, et al. Linear Motif Atlas for Phosphorylation-Dependent Signaling Sci. Signal., September 2, 2008; 1(35): ra2 - ra2. [Abstract] [Full Text] [PDF]