Functional Swapping between Transmembrane Proteins TMEM16A and TMEM16F

Variomics Screen Identifies the Re-entrant Loop of the Calcium-activated Chloride Channel ANO1 That Facilitates Channel Activation

“…Point mutations in the intracellular domains of ANO1 can point to the existence of trafficking motifs. The N terminus of ANO1 has been described to be critical for the expression and trafficking of ANO1 to the plasma membrane (41)(42)(43)(44). We identified four mutations in the N terminus that prevented ANO1 from being trafficked to the plasma membrane, opening up the possibility that these residues contribute to a noncanonical trafficking motif in ANO1 and that additional regulatory proteins bind the N terminus and are involved in regulating trafficking of the channel.…”

Structural basis for phospholipid scrambling in the TMEM16 family

“…Numerous experiments, while aimed at revealing the ion conduction path, also provide indications where the scrambling of lipids takes place. Extensive mutational studies have identified residues around the luminal entrance of the subunit cavity to influence ion conduction [47 ] and a corresponding residue in TMEM16F was shown to be involved in phospholipid scrambling [48] (Figure 2g). The mutation K584Q in TMEM16A weakens the anion selectivity of TMEM16A and the corresponding mutation Q559K in TMEM16F its selectivity for cations [41 ].…”

“…In three studies it has been attempted to create hybrid proteins of TMEM16 scramblases and TMEM16A that would gain the functional phenotype of the other protein. A first approach was performed in the Nagata lab, however the structural boundaries to fuse amino acid stretches from TMEM16A and TMEM16F were unknown at that time and the results were thus difficult to interpret [48]. Later, with structural information in hand, the Hartzell lab succeeded in converting TMEM16A into a scramblase by introducing sequence elements (the 'scrambling domain' SCRD) of TMEM16F [49 ] (Figure 2h).…”

Exposure of phosphatidylserine on the cell surface

“…Structural and chemical cross-linking analyses indicated that TMEM16F exists as a homodimer. 41,42 TMEM16F is one of the TMEM16-family proteins, also known as anoctamins; this family has 10 members (TMEM16A-H, J and K; or Ano1-10). 43 In 2008, three groups independently reported that TMEM16A, which is expressed ubiquitously, functions as a Ca 2+ -activated Cl − channel.…”