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Anchor residues in protein-protein interactions.

ABSTRACT: We show that the mechanism for molecular recognition requires one of the interacting proteins, usually the smaller of the two, to anchor a specific side chain in a structurally constrained binding groove of the other protein, providing a steric constraint that helps to stabilize a native-like bound intermediate. We identify the anchor residues in 39 protein-protein complexes and verify that, even in the absence of their interacting partners, the anchor side chains are found in conformations similar to those observed in the bound complex. These ready-made recognition motifs correspond to surface side chains that bury the largest solvent-accessible surface area after forming the complex (> or =100 A2). The existence of such anchors implies that binding pathways can avoid kinetically costly structural rearrangements at the core of the binding interface, allowing for a relatively smooth recognition process. Once anchors are docked, an induced fit process further contributes to forming the final high-affinity complex. This later stage involves flexible (solvent-exposed) side chains that latch to the encounter complex in the periphery of the binding pocket. Our results suggest that the evolutionary conservation of anchor side chains applies to the actual structure that these residues assume before the encounter complex and not just to their loci. Implications for protein docking are also discussed.

SUBMITTER: Rajamani D

PROVIDER: S-EPMC509196 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Anchor residues in protein-protein interactions.

Rajamani Deepa D Thiel Spencer S Vajda Sandor S Camacho Carlos J CJ

Proceedings of the National Academy of Sciences of the United States of America 20040721 31

We show that the mechanism for molecular recognition requires one of the interacting proteins, usually the smaller of the two, to anchor a specific side chain in a structurally constrained binding groove of the other protein, providing a steric constraint that helps to stabilize a native-like bound intermediate. We identify the anchor residues in 39 protein-protein complexes and verify that, even in the absence of their interacting partners, the anchor side chains are found in conformations simi ...[more]

PMID: 15269345

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Project description:BackgroundProtein-protein interactions are crucial for normal biological processes and to regulate cellular reactions that affect gene expression and function. Several previous studies have emphasized the roles of residues at the interface of protein-protein complexes in conferring stability and specificity to the complex. Interface residues in a protein are well known for their interactions with sidechain and main chain atoms with the interacting protein. However, the extent of intra-protein interactions involving interface residues in a protein-protein complex and their relative contribution in comparison to inter-protein interactions are not clearly understood. This paper probes this feature using a dataset of protein-protein complexes of known 3-D structure.ResultsWe have analysed a dataset of 45 transient protein-protein complex structures with at least one of the interacting proteins with a known structure available also in the unbound form. We observe that a large proportion of interface residues (1608 out of 2137 interface residues, 75%) are involved in intra and inter-protein interactions simultaneously. The amino acid propensities of such interfacial residues involved in bifurcated interactions are found to be highly similar to the general propensities to occur at protein-protein interfaces. Finally, we observe that a majority (83%) of intra-protein interactions of interface residues with bifurcated interactions, are also observed in the protein uncomplexed form.ConclusionsWe have shown, to the best of our knowledge for the first time, that a vast majority of the protein-protein interface residues are involved in extensive intra-protein interactions apart from inter-protein interactions. For a majority of such interface residues the microenvironment in the tertiary structure is pre-formed and retained upon complex formation with its cognate partner during transient interactions.ReviewersThis article was reviewed by Arumay Pal and Mallur Madhusudhan.

Dataset Information

Anchor residues in protein-protein interactions.

Publications

Anchor residues in protein-protein interactions.

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