Systematic identification of structure-specific protein–protein interactions

Author:

Holfeld Aleš,Schuster DinaORCID,Sesterhenn Fabian,Gillingham Alison KORCID,Stalder Patrick,Haenseler WaltherORCID,Barrio-Hernandez InigoORCID,Ghosh DhimanORCID,Vowles Jane,Cowley Sally AORCID,Nagel LuiseORCID,Khanppnavar BasavrajORCID,Serdiuk Tetiana,Beltrao PedroORCID,Korkhov Volodymyr MORCID,Munro SeanORCID,Riek Roland,de Souza NatalieORCID,Picotti PaolaORCID

Abstract

AbstractThe physical interactome of a protein can be altered upon perturbation, modulating cell physiology and contributing to disease. Identifying interactome differences of normal and disease states of proteins could help understand disease mechanisms, but current methods do not pinpoint structure-specific PPIs and interaction interfaces proteome-wide. We used limited proteolysis–mass spectrometry (LiP–MS) to screen for structure-specific PPIs by probing for protease susceptibility changes of proteins in cellular extracts upon treatment with specific structural states of a protein. We first demonstrated that LiP–MS detects well-characterized PPIs, including antibody–target protein interactions and interactions with membrane proteins, and that it pinpoints interfaces, including epitopes. We then applied the approach to study conformation-specific interactors of the Parkinson’s disease hallmark protein alpha-synuclein (aSyn). We identified known interactors of aSyn monomer and amyloid fibrils and provide a resource of novel putative conformation-specific aSyn interactors for validation in further studies. We also used our approach on GDP- and GTP-bound forms of two Rab GTPases, showing detection of differential candidate interactors of conformationally similar proteins. This approach is applicable to screen for structure-specific interactomes of any protein, including posttranslationally modified and unmodified, or metabolite-bound and unbound protein states.

Funder

EC | European Research Council

European Proteomics Infrastructure Consortium providing access

Parkinson Schweiz

Swiss National Science Foundation

Empiris Foundation

Oxford-McGill-Zurich Partnership in Neuroscience

UZH URPP AdaBD

Helmut Horten Stiftung

ETH Zürich Foundation

Publisher

Springer Science and Business Media LLC

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