TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells
TMEM120A, a member of the Transmembrane protein 120 (TMEM120) family, has pivotal function in adipocyte differentiation and metabolism, and may also contribute to sensing mechanical pain by functioning as an ion channel named TACAN. Here we report that expression of TMEM120A is not sufficient in mediating poking- or stretch-induced currents in cells, and have solved cryo-EM structures of human TMEM120A (HsTMEM120A) in complex with an endogenous metabolic cofactor (coenzyme A, CoASH) and in the apo form. HsTMEM120A forms a symmetrical homodimer with each monomer containing an amino-terminal coiled-coil motif followed by a transmembrane domain with six membrane-spanning helices. Within the transmembrane domain, a CoASH molecule is hosted in a deep cavity and forms specific interactions with nearby amino acid residues. Mutation of a central tryptophan residue involved in binding CoASH dramatically reduced the binding affinity of HsTMEM120A with CoASH. HsTMEM120A exhibits distinct conformations at the states with or without CoASH bound. Our results suggest that TMEM120A may have alternative functional roles potentially involved in CoASH transport, sensing or metabolism.
The structural models have been deposited in the Protein Data Bank under accession codes of 7F3T (https://www.rcsb.org/structure/7F3T) for HsTMEM120A-CoASH complex in nanodisc and 7F3U (https://www.rcsb.org/structure/7F3U) for HsTMEM120A in detergent. The cryo-EM density maps of HsTMEM120A-CoASH complex in nanodisc and HsTMEM120A in detergent have been deposited in the Electron Microscopy Data Bank under accession codes of EMD-31440 (https://www.emdataresource.org/EMD-31440) and EMD-31441 (https://www.emdataresource.org/EMD-31441), respectively.The source data files for Figure 1, Figure 1-figure supplement 1, Figure 2-figure supplement 1A, Figure 4D and Figure 4-figure supplement 3 have been provided.
Article and author information
National Natural Science Foundation of China (31925024 and 31670749)
- Zhenfeng Liu
National Natural Science Foundation of China (31825014 and 31630090)
- Bailong Xiao
the Strategic Priority Research Program of CAS (XDB37020101)
- Zhenfeng Liu
the Strategic Priority Research Program of CAS (XDB37030304)
- Yan Zhao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Andrés Jara-Oseguera, University of Texas at Austin, United States
- Preprint posted: June 17, 2021 (view preprint)
- Received: June 20, 2021
- Accepted: August 16, 2021
- Accepted Manuscript published: August 19, 2021 (version 1)
- Version of Record published: September 29, 2021 (version 2)
© 2021, Rong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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