Molecular Dynamics Simulations of a Putative Novel Mechanism for UCP1-Assisted FA Anion Transport

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22340%2F25%3A43933359" target="_blank" >RIV/60461373:22340/25:43933359 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1111/apha.70068" target="_blank" >https://doi.org/10.1111/apha.70068</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/apha.70068" target="_blank" >10.1111/apha.70068</a>

Result language

angličtina

Original language name

Molecular Dynamics Simulations of a Putative Novel Mechanism for UCP1-Assisted FA Anion Transport

Original language description

BackgroundMitochondrial energy can be stored as ATP or released as heat by uncoupling protein 1 (UCP1) during non-shivering thermogenesis in brown adipose tissue. UCP1, located in the inner mitochondrial membrane, reduces the proton gradient in the presence of long-chain fatty acids (FA). FA act as weak, protein-independent uncouplers, with the transport of the FA anion across the membrane being the rate-limiting step. According to the fatty acid cycling hypothesis, UCP1 catalyzes this step through an as-yet-undefined mechanism.MethodsWe used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis.ResultsWe identified two novel pathways for fatty acid anion translocation (sliding) at the UCP1 protein-lipid interface, ending at key arginine residues R84 and R183 in a nucleotide-binding region. This region forms a stable complex with fatty acid anion, which is crucial for anion transport. Mutations of these two arginines reduced membrane conductance, consistent with the MD simulation prediction that the arachidonic acid anion slides between helices H2-H3 and H4-H5, terminating at R84 and R183. Protonation of the arachidonic acid anion predicts its release from the protein-lipid interface, allowing it to move to either cytosolic or matrix leaflets of the membrane.ConclusionWe provide a novel, detailed mechanism by which UCP1 facilitates fatty acid anion transport, as part of the fatty acid cycling process originally proposed by Skulachev. The residues involved in this transport are conserved in other SLC25 proteins, suggesting the mechanism may extend beyond UCP1 to other members of the superfamily.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30105 - Physiology (including cytology)

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Acta Physiologica

ISSN

1748-1708

e-ISSN

1748-1716

Volume of the periodical

241

Issue of the periodical within the volume

7

Country of publishing house

GB - UNITED KINGDOM

Number of pages

15

Pages from-to

nestránkováno

UT code for WoS article

001517036800010

EID of the result in the Scopus database

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