Dataset Information

Loops govern SH2 domain specificity by controlling access to binding pockets.

ABSTRACT: Cellular functions require specific protein-protein interactions that are often mediated by modular domains that use binding pockets to engage particular sequence motifs in their partners. Yet, how different members of a domain family select for distinct sequence motifs is not fully understood. The human genome encodes 120 Src homology 2 (SH2) domains (in 110 proteins), which mediate protein-protein interactions by binding to proteins with diverse phosphotyrosine (pTyr)-containing sequences. The structure of the SH2 domain of BRDG1 bound to a peptide revealed a binding pocket that was blocked by a loop residue in most other SH2 domains. Analysis of 63 SH2 domain structures suggested that the SH2 domains contain three binding pockets, which exhibit selectivity for the three positions after the pTyr in a peptide, and that SH2 domain loops defined the accessibility and shape of these pockets. Despite sequence variability in the loops, we identified conserved structural features in the loops of SH2 domains responsible for controlling access to these surface pockets. We engineered new loops in an SH2 domain that altered specificity as predicted. Thus, selective blockage of binding subsites or pockets by surface loops provides a molecular basis by which the diverse modes of ligand recognition by the SH2 domain may have evolved and provides a framework for engineering SH2 domains and designing SH2-specific inhibitors.

SUBMITTER: Kaneko T

PROVIDER: S-EPMC6590088 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loops govern SH2 domain specificity by controlling access to binding pockets.

Kaneko Tomonori T Huang Haiming H Zhao Bing B Li Lei L Liu Huadong H Voss Courtney K CK Wu Chenggang C Schiller Martin R MR Li Shawn Shun-Cheng SS

Science signaling 20100504 120

Cellular functions require specific protein-protein interactions that are often mediated by modular domains that use binding pockets to engage particular sequence motifs in their partners. Yet, how different members of a domain family select for distinct sequence motifs is not fully understood. The human genome encodes 120 Src homology 2 (SH2) domains (in 110 proteins), which mediate protein-protein interactions by binding to proteins with diverse phosphotyrosine (pTyr)-containing sequences. The ...[more]

PMID: 20442417

Similar Datasets

Project description:Single-domain antibodies (sdAbs) are a promising class of biotherapeutics with unique structural traits within their paratope region. The distribution of canonical conformations explored by their complementarity determining region (CDR) loops differs to some extent from conventional two-chain Fv fragments of monoclonal antibodies (mAbs). In this study, we explored in detail the canonical structures of sdAb CDR-H1 and CDR-H2 loops and compared those with mAbs from the IGHV3 and IGHV1 gene families. We surveyed the antibody structures catalogued in SAbDab and clustered the CDR canonical loops in Cartesian space. While most of the sdAb clusters were sub-populations of previously defined canonical Fv conformations of CDR-H1 and CDR-H2, our stricter clustering approach defined narrower clusters in sequence-space. Meticulous visual inspection of sub-populations allowed a clearer understanding of sequence-structure relationships. The packing densities within structural pockets contacted by CDR-H1 and CDR-H2 canonical conformations were analyzed on the premise that these pockets cannot be left vacant as they would leave exposed supportive hydrophobic residues. The fine resolution of the canonical clusters defined here revealed unique signatures within these pockets, including distinct structural complementarities between CDR-H1 and CDR-H2 canonical clusters, which could not be perceived with the previous coarser clusters. We highlight examples where a single residue change in CDR-H1 sequence is sufficient to induce a dramatic population shift in CDR-H2 conformation. This suggests that preferences in combining CDR-H1 and CDR-H2 emerged naturally during antibody evolution, leading to preferred sets of conserved amino acids at key positions in the framework as well as within the CDR loops. We outline a game of musical chairs that is necessary to maintain the integrity of the antibody structures that arose during evolution. Our study also provides refined CDR-H1 and CDR-H2 structural templates for sdAb homology modeling that could be leveraged for improved antibody design.

Dataset Information

Loops govern SH2 domain specificity by controlling access to binding pockets.

Publications

Loops govern SH2 domain specificity by controlling access to binding pockets.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets