The bacterial dicarboxylate transporter VcINDY uses a two-domain elevator-type mechanism

Nature Structural & Molecular Biology
Christopher MulliganJoseph A Mindell

Abstract

Secondary transporters use alternating-access mechanisms to couple uphill substrate movement to downhill ion flux. Most known transporters use a 'rocking bundle' motion, wherein the protein moves around an immobile substrate-binding site. However, the glutamate-transporter homolog GltPh translocates its substrate-binding site vertically across the membrane, through an 'elevator' mechanism. Here, we used the 'repeat swap' approach to computationally predict the outward-facing state of the Na(+)/succinate transporter VcINDY, from Vibrio cholerae. Our model predicts a substantial elevator-like movement of VcINDY's substrate-binding site, with a vertical translation of ~15 Å and a rotation of ~43°. Our observation that multiple disulfide cross-links completely inhibit transport provides experimental confirmation of the model and demonstrates that such movement is essential. In contrast, cross-links across the VcINDY dimer interface preserve transport, thus revealing an absence of large-scale coupling between protomers.

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Citations

Sep 8, 2016·Proceedings of the National Academy of Sciences of the United States of America·Bryan H Thurtle-Schmidt, Robert M Stroud
Jan 26, 2017·ELife·Gabriel A FitzgeraldJoseph A Mindell
Feb 20, 2017·Biochemical Pharmacology·Marie-Laure RivesAlan D Wickenden
Jan 31, 2018·Nature Structural & Molecular Biology·Yunpeng Zhou, John H Bushweller
Nov 24, 2017·The Journal of General Physiology·Emel FiciciLucy R Forrest
Jun 12, 2018·ELife·Erika A RiedererFrancis I Valiyaveetil
Jul 8, 2018·Clinical Pharmacology and Therapeutics·Avner SchlessingerPär Matsson
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May 3, 2019·Nature Communications·Yung-Ning ChangEric R Geertsma
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Mar 11, 2020·The Journal of Biological Chemistry·Ahlam KhamaysiEhud Ohana
Jun 24, 2020·Biochemical Society Transactions·Katharina Holzhüter, Eric R Geertsma
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Oct 14, 2020·ELife·Adam W Duster, Hai Lin
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Aug 18, 2021·The FEBS Journal·David B SauerDa-Neng Wang
Nov 10, 2021·Physical Chemistry Chemical Physics : PCCP·Huaichuan DuanJianping Hu

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Methods Mentioned

BETA
X-ray
Size Exclusion Chromatography

Software Mentioned

Mascot Distiller
MODELLER
OPM
Mascot Server
ConSurf
SymD
PyMOL
VcINDY
Mascot Daemon
DSSP

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