Figure 4.

Proposed secondary structures for anoctamin-1 (ANO1), or TMEM16A. A, Original model, based on predicted hydropathy profiles, describing the basic membrane topology of the protein, which comprises 8 transmembrane domains (TMDs), C- and N-terminal ends located in the cytoplasm, and a pore loop located between TMD5 and TMD6.^13,15 B, Revised model proposing that the extracellular loop following TMD5 in the original model may instead face the cytoplasm.¹⁰³ C, More detailed map of the revised membrane topology model of ANO1, revealing the locations and amino acid sequences of the 4 known spliced variants (a–d), the identification of 2 glutamate residues at positions 702 and 705 in mouse as potential Ca²⁺ binding sites,¹⁰³ the location and hypothetical function of 3 classes of calmodulin (CaM)-binding domains (CaM-BD1 and CaM-BD2,¹⁰⁴ CMB1 and CMB2,¹⁰⁵ and regulatory CaM-binding motif [RCMB]¹⁰⁶), and at least one N-glycosylation site (N-Glycos). The structure also exposes the location of 4 consecutive glutamate residues immediately proximal to spliced variant c, which were shown to be critical for Ca²⁺- and voltage-dependent gating of the channel.¹⁰⁷