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Structure. 2017 Oct 3;25(10):1598-1610.e3. doi: 10.1016/j.str.2017.07.017. Epub 2017 Sep 7.

Comprehensive Analysis of the Human SH3 Domain Family Reveals a Wide Variety of Non-canonical Specificities.

Author information

1
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
2
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
3
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada.
4
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
5
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
6
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
7
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada.
8
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: sachdev.sidhu@utoronto.ca.

Abstract

SH3 domains are protein modules that mediate protein-protein interactions in many eukaryotic signal transduction pathways. The majority of SH3 domains studied thus far act by binding to proline-rich sequences in partner proteins, but a growing number of studies have revealed alternative recognition mechanisms. We have comprehensively surveyed the specificity landscape of human SH3 domains in an unbiased manner using peptide-phage display and deep sequencing. Based on ∼70,000 unique binding peptides, we obtained 154 specificity profiles for 115 SH3 domains, which reveal that roughly half of the SH3 domains exhibit non-canonical specificities and collectively recognize a wide variety of peptide motifs, most of which were previously unknown. Crystal structures of SH3 domains with two distinct non-canonical specificities revealed novel peptide-binding modes through an extended surface outside of the canonical proline-binding site. Our results constitute a significant contribution toward a complete understanding of the mechanisms underlying SH3-mediated cellular responses.

KEYWORDS:

ITSN1; SH3 domain; SORBS2; atypical binding; deep sequencing; domain specificity; peptide library; peptide motif; peptide-recognition module; phage display

PMID:
28890361
DOI:
10.1016/j.str.2017.07.017
[Indexed for MEDLINE]
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