ATP8A2 Membrane Protein Introduction

Introduction of ATP8A2

ATP8A2 is encoded by ATP8A2 gene. It belongs to the P(4)-ATPase subfamily of P-type ATPases, which are involved in the transport of amino phospholipids. P(4)-ATPases determine the curvature of the phospholipid bilayer by flipping amino phospholipids from the exoplasmic to the cytoplasmic leaflet. Recent studies conducted on ATP8A2 suggest it is related to various diseases, include Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 4. In this condition, ATP8A2 has been considered as a promising molecular diagnostic marker and novel therapeutic targets in the clinic.

Function of ATP8A2 Membrane Protein

ATP8A2 is a P4-ATPase that flips phosphatidylserine and phosphatidylethanolamine across cell membranes. This generates membrane phospholipid asymmetry, a property important in many cellular processes, including vesicle trafficking. ATP8A2 is predicted to contain an E1 E2 ATPase, a haloacid dehalogenase-like hydrolase (HAD) domain, and multiple transmembrane domains. Associations between this protein and cell cycle control protein 50A are important for translocation of phosphatidylserine across membranes. Mutations in this gene have been associated with a syndrome (CAMRQ4) characterized by cerebellar ataxia and cognitive disabilities.

Fig.1 Generation of the ATP8A2-knockout Mouse. (Coleman, 2014)

Application of ATP8A2 Membrane Protein in Literature

1. Chalat M., et al. C-terminus of the P4-ATPase ATP8A2 functions in protein folding and regulation of phospholipid flippase activity. Mol Biol Cell. 2017, 28(3): 452-462. PubMed ID: 27932490
   
   

   This article reports that the role of the C-terminus of ATP8A2 in its expression, subcellular localization, interaction with its subunit CDC50A, and function as a phosphatidylserine flippase. The data show the C-terminus plays an important role in the efficient folding and regulation of ATP8A2.

2. Martín-Hernández E., et al. New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy. Neurogenetics. 2016, 17(4): 259-263. PubMed ID: 27679995
   
   

   This article reveals that a homozygous mutation of ATP8A2 gene by Whole exome sequencing (WES). These results indicate ATP8A2 gene mutations may be associated with some diseases.

3. Vestergaard A.L., et al. Specific mutations in mammalian P4-ATPase ATP8A2 catalytic subunit entail differential glycosylation of the accessory CDC50A subunit. FEBS Lett. 2015, 589(24 Pt B): 3908-14. PubMed ID: 26592152
   
   

   Authors in this group conduct an extensive mutational alanine screening of the mammalian flippase ATP8A2 catalytic subunit. The results indicate that ATP8A2 mutations can lead to reduced glycosylation of the accessory subunit CDC50A. Besides, these mutations may disturb the interaction between the subunits.

4. McMillan H.J., et al. Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy. Orphanet J Rare Dis. 2018, 13(1): 86. PubMed ID: 30012219
   
   

   This article analyses the clinical phenotype of patients with ATP8A2 mutations in multiple diagnostic centers. The results demonstrate that eleven patients with ATP8A2 mutations present different symptoms in clinic, such as developmental delay, severe hypotonia and movement disorders. Meanwhile, ATP8A2 mutations should be contribute to the early diagnosis of neurologic disorders.

5. Coleman J.A., et al. Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival. J Cell Sci. 2014, 127(Pt 5): 1138-49. PubMed ID: 24413176
   
   

   Authors in this article determine the role of ATP8A2 in sensory systems by using the ATP8A2-deficient mice model. The data suggest that ATP8A2 plays a key role in the function and survival of photoreceptor cells and spiral ganglion cells by maintaining the composition of phospholipids and promoting the transfer of vesicles.

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Reference

1. Coleman J.A, et al. (2014). Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival. J Cell Sci. 127(Pt 5): 1138-49.

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