title: TMEM16 proteins: unknown structure and confusing functions.
abstract: The TMEM16 family of membrane proteins, also known as anoctamins, plays key roles in a variety of physiological functions that range from ion transport to phospholipid scrambling and to regulating other ion channels. The first two family members to be functionally characterized, TMEM16A (ANO1) and TMEM16B (ANO2), form Ca(2+)-activated Cl(-) channels and are important for transepithelial ion transport, olfaction, phototransduction, smooth muscle contraction, nociception, cell proliferation and control of neuronal excitability. The roles of other family members, such as TMEM16C (ANO3), TMEM16D (ANO4), TMEM16F (ANO6), TMEM16G (ANO7) and TMEM16J (ANO9), remain poorly understood and controversial. These homologues were reported to be phospholipid scramblases, ion channels, to have both functions or to be regulatory subunits of other channels. Mutations in TMEM16F cause Scott syndrome, a bleeding disorder caused by impaired Ca(2+)-dependent externalization of phosphatidylserine in activated platelets, suggesting that this homologue might be a scramblase. However, overexpression of TMEM16F has also been associated with a remarkable number of different ion channel types, raising the possibility that this protein might be involved in both ion and lipid transports. The recent identification of an ancestral TMEM16 homologue with intrinsic channel and scramblase activities supports this hypothesis. Thus, the TMEM16 family might have diverged in two or three different subclasses, channels, scramblases and dual-function channel/scramblases. The structural bases and functional implication of such a functional diversity within a single protein family remain to be elucidated and the links between TMEM16 functions and human physiology and pathologies need to be investigated.
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Picollo
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Mattia
authors.initials: M
authors.lastname: Malvezzi
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: ala2022@med.cornell.edu.
authors.forename: Alessio
authors.initials: A
authors.lastname: Accardi
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D018118:Chloride Channels / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D049990:Membrane Transport Modulators / Q000737:chemistry / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D015398:Signal Transduction
chemical_list: C476213:ANO1 protein, human; C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D049990:Membrane Transport Modulators; D009363:Neoplasm Proteins
keywords: Ca(2+)-activated Cl(−) channels; Ca(2+)-dependent phospholipid scrambling; anoctamin; membrane proteins; reconstitution