1. Structural basis of client specificity in mitochondrial membrane-protein chaperones
- Author
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Yong Wang, Ons Dakhlaoui, Tobias Jores, Kresten Lindorff-Larsen, Martha Brennich, Doriane Costa, Doron Rapaport, Katharina Weinhäupl, Paul Schanda, Audrey Hessel, Iva Sučec, Beate Bersch, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Linderstrøm-Lang Centre for Protein Science [Copenhagen], IT University of Copenhagen (ITU), University of Tübingen, European Molecular Biology Laboratory [Grenoble] (EMBL), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-18-CE92-0032,MitoMemProtImp,Etudes structurales et fonctionnelles de l'import et le transfert à travers l'espace inter-membranaire des protéines membranaires mitochondriales(2018), University of Copenhagen = Københavns Universitet (KU), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of Copenhagen = Københavns Universitet (UCPH), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and IT University of Copenhagen
- Subjects
DEAFNESS DYSTONIA SYNDROME ,010402 general chemistry ,01 natural sciences ,Hydrophobic effect ,03 medical and health sciences ,Molecular dynamics ,0302 clinical medicine ,X-Ray Diffraction ,BINDING ,Mitochondrial Precursor Protein Import Complex Proteins ,Scattering, Small Angle ,Humans ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Integral membrane protein ,IN-VIVO ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Chemistry ,IMPORT ,INTERMEMBRANE SPACE ,Membrane Proteins ,Mitochondrial carrier ,Transmembrane protein ,SIMULATIONS ,SUBSTRATE-SPECIFICITY ,0104 chemical sciences ,MOLECULAR-DYNAMICS ,BEAMLINE ,Mitochondrial Membrane Protein ,Mitochondrial Membranes ,Biophysics ,COMPLEXES ,Protein folding ,030217 neurology & neurosurgery ,Molecular Chaperones - Abstract
Chaperones are essential for assisting protein folding and for transferring poorly soluble proteins to their functional locations within cells. Hydrophobic interactions drive promiscuous chaperone-client binding, but our understanding of how additional interactions enable client specificity is sparse. Here, we decipher what determines binding of two chaperones (TIM8 center dot 13 and TIM9 center dot 10) to different integral membrane proteins, the all-transmembrane mitochondrial carrier Ggc1 and Tim23, which has an additional disordered hydrophilic domain. Combining NMR, SAXS, and molecular dynamics simulations, we determine the structures of Tim23/TIM8 center dot 13 and Tim23/TIM9 center dot 10 complexes. TIM8 center dot 13 uses transient salt bridges to interact with the hydrophilic part of its client, but its interactions to the transmembrane part are weaker than in TIM9 center dot 10. Consequently, TIM9 center dot 10 outcompetes TIM8 center dot 13 in binding hydrophobic clients, while TIM8 center dot 13 is tuned to few clients with both hydrophilic and hydrophobic parts. Our study exemplifies how chaperones fine-tune the balance of promiscuity versus specificity.
- Published
- 2020
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