Polymodal Control of TMEM16x Channels and Scramblases

Figures

• 

  Figure 1. Topological diagram of TMEM16x proteins, showing the position of the alternative spliced exons and a range of functional domains. The boxes (broken lines) highlight the TMs involved in the formation of the ion/lipid pathways in TMEM16x. The approximate position of each splicing variant is labelled using the nomenclature described in the main text. The diagrams also show the approximate position of a range of functional domains, including (1) the principal Ca2+-binding pocket, which encompasses conserved acidic residues located in TM6-8; (2) additional regulatory Ca2+-binding sites; (3) putative calmodulin (CaM)-binding sites; (4) putative phosphatidylinositol 4,5-bisphosphate (PIP2)-binding sites; and (5) the pH-sensitive domain on the extracellular loop between TM5 and TM6 of TMEM16A.

• 

  Figure 2. Structural alignment of the experimentally determined Ca2+-bound structure of TMEM16A channel, and a model of the TMEM16A channel in the open state. (A) Left: Lateral view of the dimeric Ca2+-bound TMEM16A cryo-EM structure (PDB ID: 5OYB, blue). Right: TMEM16A open-state model (from [122], grey). The Ca2+ ions are shown in green. (B) Left: Single monomer of the Ca2+-bound TMEM16A cryo-EM structure (5OYB, blue), aligned with the open-state model (grey) [122]. The Ca2+ ions are shown in green. Right: Magnification of the gate-forming pore residues (V539 and I636, from [122]), in the Ca2+-bound TMEM16A cryo-EM structure (5OYB, blue), and of the TMEM16A open-state model (grey) [122], as indicated.

• 

  Figure 3. TMEM16A close and open conformation diagram. Diagrammatic representation of a single TMEM16A channel pore and related gating mechanisms. Ca2+ binding induces opening of the steric gate in TM6 and attenuation of the electrostatic gate. The movement of the TM6 helix during gating is represented as a tilt of the inner portion of the pore and opening of the outer pore. The green and red backgrounds depict positive and negative electrostatic potentials in the pore, respectively.

• 

  Figure 4. Summary of the principal factors that control TMEM16x function. Schematic representation of various physiological modulators of TMEM16x activity. A TMEM16x protein in the plasma membrane of a generic cell is shown in blue. Factors that control TMEM16x activity are connected to the protein with red or blue lines to denote inhibitory or stimulatory influences, respectively. The black dashed arrows indicate the modulations for which an underlying mechanism has not yet been fully defined and/or conflicting evidence has been proposed.