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A litmus test for classifying recognition mechanisms of transiently binding proteins.

ABSTRACT: Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conformational selection prevails on ubiquitin's paradigmatic interaction with an SH3 (Src-homology 3) domain. By contrast, the SH3 domain recognizes ubiquitin in a two-state binding process. Subsequent molecular dynamics simulations and Markov state modeling reveal that the ubiquitin conformation selected for binding exhibits a characteristically extended C-terminus. Our framework is robust and expandable for implementation in other binding scenarios with the potential to show that conformational selection might be the design principle of the hubs in protein interaction networks.

SUBMITTER: Chakrabarti KS

PROVIDER: S-EPMC9249894 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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A litmus test for classifying recognition mechanisms of transiently binding proteins.

Chakrabarti Kalyan S KS Olsson Simon S Pratihar Supriya S Giller Karin K Overkamp Kerstin K Lee Ko On KO Gapsys Vytautas V Ryu Kyoung-Seok KS de Groot Bert L BL Noé Frank F Becker Stefan S Lee Donghan D Weikl Thomas R TR Griesinger Christian C

Nature communications 20220701 1

Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conf ...[more]

PMID: 35778416

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Dataset Information

A litmus test for classifying recognition mechanisms of transiently binding proteins.

Publications

A litmus test for classifying recognition mechanisms of transiently binding proteins.

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