Conformational changes in the Niemann–Pick type C1 protein NCR1 drive sterol translocation

Author:

Frain Kelly M.1ORCID,Dedic Emil1ORCID,Nel Lynette1ORCID,Bohush Anastasiia12ORCID,Olesen Esben1,Thaysen Katja3ORCID,Wüstner Daniel3,Stokes David L.4ORCID,Pedersen Bjørn Panyella1ORCID

Affiliation:

1. Department of Molecular Biology and Genetics, Aarhus University, Aarhus C 8000, Denmark

2. Department of Molecular Biology and Genetics, Aarhus Institute of Advanced Studies, Aarhus University, Aarhus C 8000, Denmark

3. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M 5230, Denmark

4. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016

Abstract

The membrane protein Niemann–Pick type C1 (NPC1, named NCR1 in yeast) is central to sterol homeostasis in eukaryotes. Saccharomyces cerevisiae NCR1 is localized to the vacuolar membrane, where it is suggested to carry sterols across the protective glycocalyx and deposit them into the vacuolar membrane. However, documentation of a vacuolar glycocalyx in fungi is lacking, and the mechanism for sterol translocation has remained unclear. Here, we provide evidence supporting the presence of a glycocalyx in isolated S. cerevisiae vacuoles and report four cryo-EM structures of NCR1 in two distinct conformations, named tense and relaxed. These two conformations illustrate the movement of sterols through a tunnel formed by the luminal domains, thus bypassing the barrier presented by the glycocalyx. Based on these structures and on comparison with other members of the Resistance–Nodulation–Division (RND) superfamily, we propose a transport model that links changes in the luminal domains with a cycle of protonation and deprotonation within the transmembrane region of the protein. Our model suggests that NPC proteins work by a generalized RND mechanism where the proton motive force drives conformational changes in the transmembrane domains that are allosterically coupled to luminal/extracellular domains to promote sterol transport.

Funder

EC | ERC | HORIZON EUROPE European Research Council

Natur og Univers, Det Frie Forskningsråd

Carlsbergfondet

HHS | National Institutes of Health

SARU fellowship

AUFF-Ukraine Research Fellowship

Publisher

Proceedings of the National Academy of Sciences

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