TMEM16 Membrane Proteins in Health and Disease

The TransMEMbrane protein 16 (TMEM16) family has received much attention since the discovery of TMEM16A as the long sought-after calcium-activated chloride channels (CaCCs) in 2008. In mammals the TMEM16 family comprises 10 members, which are widely expressed and thus far have been associated with two main functions: serving as ion channels to transport ions across cell membranes and as lipid scramblases to catalyze phospholipid transposition between the two leaflets of the cell membrane. Recent structural and functional studies have greatly advanced our understanding of the TMEM16 proteins at the molecular level. The calcium-binding sites are highly conserved throughout the mammalian TMEM16 family and their eukaryotic homologs, implying that calcium-dependent activation might be a common characteristic of TMEM16 proteins. Unlike potassium channels, TMEM16 channels display a low level of ion selectivity. Some TMEM16 family members may even have both ion channel and lipid scramblase activities, suggesting that the ancestors of TMEM16 proteins might have evolved mechanisms to allow various ionic and lipid substrates to go through, thereby rendering them dual functionalities. The current understanding of the structure-function of TMEM16 proteins, their physiological functions, and potential pathological roles in human disease are summarized in this chapter.

Duke Scholars

Author Huanghe Yang Biochemistry