Diversity in the SH2 domain family phosphotyrosyl peptide binding site.
Src homology 2 (SH2) domains are approximately 100 residue phosphotyrosyl peptide binding modules found in signalling proteins and are important targets for therapeutic intervention. The peptide binding site is evolutionarily well conserved, particularly at the two major binding pockets, pTyr and pTyr + 3. We present a computational analysis of diversity within the peptide binding region and discuss molecular recognition beyond the conventional binding motif, drawing attention to novel conserved ligand interaction sites which may be exploitable in ligand binding studies. The peptide binding site is defined by selecting crystal contacts and domains are clustered according to binding site residue similarity. Comparison with a classification based on experimental peptide screening reveals a high level of qualitative agreement, indicating that the method is able independently to generate functional information. A conservation scoring method reveals extensive patches of conservation in some groups not present across the whole family, challenging the notion that the domains recognise only a linear phosphopeptide sequence. Conservation difference maps determine group-dependent clusters of conserved residues that are not seen when considering a larger experimentally determined group. Many of these residues contact the peptide outside the pTyr to pTyr + 3 motif, challenging the conventional view that this motif is largely responsible for ligand recognition and discrimination.
Campbell
S J
SJ
School of Biochemistry and Molecular Biology, Garstang Building, University of Leeds, Leeds LS2 9JT, UK.
Jackson
R M
RM
D000595:Amino Acid Sequence; D001665:Binding Sites; D019143:Evolution, Molecular; D014644:Genetic Variation; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism*; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D018909:src Homology Domains / Q000235:genetics* / Q000502:physiology
D008024:Ligands; D010455:Peptides; D019000:Phosphotyrosine