RT Journal Article
SR Electronic
T1 TMEM16 and OSCA/TMEM63 proteins share a conserved potential to permeate ions and phospholipids
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.02.04.578431
DO 10.1101/2024.02.04.578431
A1 Lowry, Augustus J.
A1 Liang, Pengfei
A1 Song, Mo
A1 Wan, Y.C. Serena
A1 Pei, Zhen-Ming
A1 Yang, Huanghe
A1 Zhang, Yang
YR 2024
UL http://biorxiv.org/content/early/2024/09/03/2024.02.04.578431.abstract
AB The calcium-activated TMEM16 proteins and the mechanosensitive/osmolarity-activated OSCA/TMEM63 proteins belong to the Transmembrane Channel/Scramblase (TCS) superfamily. Within the superfamily, OSCA/TMEM63 proteins, as well as TMEM16A and TMEM16B, are thought to function solely as ion channels. However, most TMEM16 members, including TMEM16F, maintain an additional function as scramblases, rapidly exchanging phospholipids between leaflets of the membrane. Although recent studies have advanced our understanding of TCS structure-function relationships, the molecular determinants of TCS ion and lipid permeation remain unclear. Here we show that single mutations along the transmembrane helix (TM) 4/6 interface allow non-scrambling TCS members to permeate phospholipids. In particular, this study highlights the key role of TM 4 in controlling TCS ion and lipid permeation and offers novel insights into the evolution of the TCS superfamily, suggesting that, like TMEM16s, the OSCA/TMEM63 family maintains a conserved potential to permeate ions and phospholipids.Competing Interest StatementThe authors have declared no competing interest.