SH2 domains recognize contextual peptide sequence information to determine selectivity.
Selective ligand recognition by modular protein interaction domains is a primary determinant of specificity in signaling pathways. Src homology 2 (SH2) domains fulfill this capacity immediately downstream of tyrosine kinases, acting to recruit their host polypeptides to ligand proteins harboring phosphorylated tyrosine residues. The degree to which SH2 domains are selective and the mechanisms underlying selectivity are fundamental to understanding phosphotyrosine signaling networks. An examination of interactions between 50 SH2 domains and a set of 192 phosphotyrosine peptides corresponding to physiological motifs within FGF, insulin, and IGF-1 receptor pathways indicates that individual SH2 domains have distinct recognition properties and exhibit a remarkable degree of selectivity beyond that predicted by previously described binding motifs. The underlying basis for such selectivity is the ability of SH2 domains to recognize both permissive amino acid residues that enhance binding and non-permissive amino acid residues that oppose binding in the vicinity of the essential phosphotyrosine. Neighboring positions affect one another so local sequence context matters to SH2 domains. This complex linguistics allows SH2 domains to distinguish subtle differences in peptide ligands. This newly appreciated contextual dependence substantially increases the accessible information content embedded in the peptide ligands that can be effectively integrated to determine binding. This concept may serve more broadly as a paradigm for subtle recognition of physiological ligands by protein interaction domains.
Liu
Bernard A
BA
Ben May Department for Cancer Research and Committee on Cancer Biology, The University of Chicago, Chicago, Illinois 60637, USA.
Jablonowski
Karl
K
Shah
Eshana E
EE
Engelmann
Brett W
BW
Jones
Richard B
RB
Nash
Piers D
PD
D000595:Amino Acid Sequence; D000818:Animals; D016000:Cluster Analysis; D006801:Humans; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics*; D011485:Protein Binding; D016415:Sequence Alignment; D017421:Sequence Analysis; D018909:src Homology Domains
D010455:Peptides