Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
Yan Han
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
Hamid Baniasadi
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
Weizhong Zeng
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
Jimin Pei
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
Nick V Grishin
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
Junmei Wang
Department of pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
TMEM120A, also named as TACAN, is a novel membrane protein highly conserved in vertebrates and was recently proposed to be a mechanosensitive channel involved in sensing mechanical pain. Here we present the single-particle cryogenic electron microscopy (cryo-EM) structure of human TMEM120A, which forms a tightly packed dimer with extensive interactions mediated by the N-terminal coiled coil domain (CCD), the C-terminal transmembrane domain (TMD), and the re-entrant loop between the two domains. The TMD of each TMEM120A subunit contains six transmembrane helices (TMs) and has no clear structural feature of a channel protein. Instead, the six TMs form an α-barrel with a deep pocket where a coenzyme A (CoA) molecule is bound. Intriguingly, some structural features of TMEM120A resemble those of elongase for very long-chain fatty acids (ELOVL) despite the low sequence homology between them, pointing to the possibility that TMEM120A may function as an enzyme for fatty acid metabolism, rather than a mechanosensitive channel.
