2026-04-17T15:56:49Zhttps://recercat.cat/oai/request
oai:recercat.cat:10230/530772025-12-12T03:34:53Zcom_2072_6col_2072_452952
RECERCAT author Faure, Andre J. author Domingo Espinós, Júlia, 1991- author Schmiedel, Jörn M. author Hidalgo-Carcedo, Cristina author Diss, Guillaume author Lehner, Ben, 1978- 2022-05-13T07:37:29Z2022 Allosteric communication between distant sites in proteins is central to biological regulation but still poorly characterized, limiting understanding, engineering and drug development1-6. An important reason for this is the lack of methods to comprehensively quantify allostery in diverse proteins. Here we address this shortcoming and present a method that uses deep mutational scanning to globally map allostery. The approach uses an efficient experimental design to infer en masse the causal biophysical effects of mutations by quantifying multiple molecular phenotypes-here we examine binding and protein abundance-in multiple genetic backgrounds and fitting thermodynamic models using neural networks. We apply the approach to two of the most common protein interaction domains found in humans, an SH3 domain and a PDZ domain, to produce comprehensive atlases of allosteric communication. Allosteric mutations are abundant, with a large mutational target space of network-altering 'edgetic' variants. Mutations are more likely to be allosteric closer to binding interfaces, at glycine residues and at specific residues connecting to an opposite surface within the PDZ domain. This general approach of quantifying mutational effects for multiple molecular phenotypes and in multiple genetic backgrounds should enable the energetic and allosteric landscapes of many proteins to be rapidly and comprehensively mapped.This work was funded by European Research Council (ERC) Advanced (883742) and Consolidator (616434) grants, the Spanish Ministry of Science and Innovation (PID2020-118723GB-I00, BFU2017-89488-P, EMBL Partnership, Severo Ochoa Centre of Excellence), the Bettencourt Schueller Foundation, the AXA Research Fund, Agencia de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322), and the CERCA Program/Generalitat de Catalunya. J.M.S. was supported by an EMBO Long-Term Fellowship (ALTF 857-2016) and a Marie Skłodowska-Curie Fellowship (752809, EU Commission Horizon 2020) © Andre J. Faure et al, under exclusive licence to Springer Nature Limited 2022 info:eu-repo/semantics/openAccess Proteïnes Control per retroacció (Biologia) Fenotip Genètica Mutacions Mapping the energetic and allosteric landscapes of protein binding domains. info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion