Structural basis of client specificity in mitochondrial membrane-protein chaperones
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Structural basis of client specificity in mitochondrial membrane-protein chaperones. / Sučec, Iva; Wang, Yong; Dakhlaoui, Ons; Weinhäupl, Katharina; Jores, Tobias; Costa, Doriane; Hessel, Audrey; Brennich, Martha; Rapaport, Doron; Lindorff-Larsen, Kresten; Bersch, Beate; Schanda, Paul.
I: Science Advances, Bind 6, Nr. 51, eabd0263, 2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Structural basis of client specificity in mitochondrial membrane-protein chaperones
AU - Sučec, Iva
AU - Wang, Yong
AU - Dakhlaoui, Ons
AU - Weinhäupl, Katharina
AU - Jores, Tobias
AU - Costa, Doriane
AU - Hessel, Audrey
AU - Brennich, Martha
AU - Rapaport, Doron
AU - Lindorff-Larsen, Kresten
AU - Bersch, Beate
AU - Schanda, Paul
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - DEAFNESS DYSTONIA SYNDROME
KW - SUBSTRATE-SPECIFICITY
KW - INTERMEMBRANE SPACE
KW - MOLECULAR-DYNAMICS
KW - IN-VIVO
KW - IMPORT
KW - BINDING
KW - COMPLEXES
KW - SIMULATIONS
KW - BEAMLINE
U2 - 10.1126/sciadv.abd0263
DO - 10.1126/sciadv.abd0263
M3 - Journal article
C2 - 33355130
VL - 6
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 51
M1 - eabd0263
ER -
ID: 254726776