ANO4 Membrane Protein Introduction

Introduction of ANO4

ANO4 is encoded by the ANO4 gene and is also known as transmembrane protein 16D (TMEM16D). It belongs to the transmembrane protein 16 (TMEM16) family which is a large family of membrane proteins and is highly conserved in different eukaryotic organisms from fungi to invertebrate to mammals. TMEM16 family is also known as lipid scramblases because it moves lipids between the two layers of the membrane. Meanwhile, it was concluded that ANO4 has 8 transmembrane helices according to the structure of the fungal homolog nhTMEM16.

Function of ANO4 Membrane Protein

The activity of ANO4 is activated by sub-micromolar Ca²⁺ concentration, which is a shared characteristic of TMEM16 proteins. The underlying regulatory ligand binding site and some of the interacting residues of Ca²⁺ binding have not been identified so far. ANO4 is a member of the TMEM16 family, which is negatively charged chloride ion. The structure of ANO4 has not been reported so far. However, the biochemical analysis in the ANO4 expressing cells shows that the whole-cell currents of variable magnitudes are activated by ATP and the activation of ANO4 by ATP can induce the increase of the intracellular Ca²⁺. The increase of Ca²⁺ may not only activate the Cl⁻ channel, but may also trigger the inhibition of anoctamins via CAMKI, which may actually counteract further activation. For all anoctamins except of ANO4, membrane voltages were depolarized through stimulation of purinergic receptors and increase of Ca²⁺, which is expected upon increase of a Cl⁻ conductance along with cation influx through store-operated Ca²⁺ channels.

Fig.1 Proposed structure of ANO4 membrane protein (Paulino, 2017)

Application of ANO4 Membrane Protein in Literature

1. Tian Y., et al. (2012) Anoctamins are a family of Ca²⁺-activated Cl-channels. J. Cell Sci. 2012, 125(21):4991. PubMed ID: 22946059
   
   

   This article reports that in the ANO4 expressing cells, the whole-cell currents of variable magnitudes are activated by ATP and the activation of ANO4 by ATP can induce the increase of the intracellular Ca²⁺. The increase of Ca²⁺ may not only activate the Cl⁻ channel, but may also trigger the inhibition of anoctamins via CAMKI, which may actually counteract further activation.

2. Hartzell H.C., et al. Anoctamin/TMEM16 family members are Ca²⁺-activated Cl⁻ channels. The Journal of Physiology. 2009, 587(10):2127-2139. PubMed ID: 19015192
   
   

   This article reveals that the anoctamin family exhibits characteristics most similar to those expected for the classical Ca²⁺-activated Cl⁻ channels proteins, which perform many important functions in cell physiology processes.

3. Paulino C., et al. Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A. eLife. 2017, 6:e26232. PubMed ID: 28561733
   
   

   Authors in this group apply cryo-electron microscopy and a complementary functional characterization to reveal the structural basis of anion conduction in a TMEM16 channel and it defines the foundation for the diverse functional behavior in the TMEM16 family.

4. Gyobu S., et al. Characterization of the scrambling domain of the TMEM16 family. Proceedings of the National Academy of Sciences. 2017, 114(24):6274. PubMed ID: 28559311
   
   

   The results of this article suggest that TMEM16 provides a cleft containing hydrophilic "stepping stones" for the outward translocation of phospholipids.

5. Brunner J.D., et al. Structural basis for phospholipid scrambling in the TMEM16 family. Curr. Opin. Struct. Biol. 2016, 39:61-70. PubMed ID: 27295354
   
   

   This article focuses on the X-ray structure of a fungal TMEM16 homologue, which can provide insight into the architecture of this protein family and into potential scrambling mechanisms.

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Reference

1. Paulino C., et al. (2017). Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A. eLife. 6:e26232.

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