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2.A.106 Ca2+:H+ Antiporter-2 (CaCA2) Family

The PF27 family (SwissProt family UPF0016; Prosite entry PDOC00934) is a small family of proteins found in bacteria, archaea, yeast, plants and animals. They are usually 200-350 amino acyl residues long and exhibit 5-7 TMSs. Congenital Disorders of Glycosylation (CDG) are rare inherited diseases causing glycosylation defects responsible for severe growth and psychomotor retardations in patients. TMEM165 has been implicated in both Golgi vesicular trafficking and ion homeostasis. TMEM165 deficient mammalian cells or yeast cells deficient in Gtd1p, the yeast TMEM165 ortholog suggest that TMEM165 is a transporter involved in ion homeostasis (Dulary et al. 2017). Several studies indicate that TMEM165 is a Golgi localized Ca2+/H+ and/or Mn2+/H+ antiporter. Possibly TMEM165 proteins are Mn2+ transporters essential to achieve the correct N-glycosylation process of proteins in the secretory pathway.

Defects in the human TMEM165 homologue are the cause of congenital disorder of glycosylation type 2K (CDG2K), an autosomal recessive disorder with variable phenotypes (Foulquier et al.2012). Affected individuals show psychomotor and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Congenital disorders of glycosylation are caused by a defect in glycoprotein biosynthesis and are characterized by under-glycosylated serum glycoproteins and a wide variety of clinical features. The broad spectrum of features may reflect the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions (Foulquier et al. 2012).

The Ca2+:H+  Antiporter (CaCA2) Family (previous called the uncharacterized Protein Family 0016 (UPF0016), is well conserved throughout prokaryotes and eukaryotes. The yeast golgi Gcr1-dependent translation factor 1 protein (Gdt1p) contributes to Ca2+ homeostasis. A yeast gdt1 mutant was found to be sensitive to high concentrations of Ca2+, and this sensitivity was suppressed by expression of human TMEM165 in yeast (Demaegd et al.2013). Patch-clamp analyses on human cells indicated that TMEM165 catalyzes Ca2+ transport, and defects in TMEM165 affected both Ca2+ and pH homeostasis.Gdt1p and TMEM165 are probably Golgi-localized Ca2+:H+  antiporters. Modification of the Golgi Ca2+ and pH balance could explain the glycosylation defects observed in TMEM165-deficient patients. 

The UPF0016 family is defined by the presence of 1 or 2 copies of the E-phi-G-D-[KR]-[TS] consensus motif in their transmembrane domain. Colinet et al. 2017 showed that 2 members of this family, the human TMEM165 and the budding yeast Gdt1p, are functionally related Ca2+ transporters. Mutations in TMEM165 cause a type of rare human genetic diseases called Congenital Disorders of Glycosylation. Mutations in the yeast Golgi-localized Ca2+ transporter, Gdt1, revealed that acidic and polar uncharged residues of the consensus motifs are involved in calcium tolerance and calcium transport activity. The E53 residue corresponds to the mutation in humans that triggers congenital disorders of glycosylation (Colinet et al. 2017).

The generalized reaction catalyzed by CaCA2 family members is:

Ca2+ (cytoplasm) + H+ (golgi lumen) → Ca2+ (golgi lumen) + H+ (cytoplasm)

This family belongs to the: LysE Superfamily.

References associated with 2.A.106 family:

Colinet, A.S., L. Thines, A. Deschamps, G. Flémal, D. Demaegd, and P. Morsomme. (2017). Acidic and uncharged polar residues in the consensus motifs of the yeast Ca2+ transporter Gdt1p are required for calcium transport. Cell Microbiol. [Epub: Ahead of Print] 28114750
Demaegd, D., F. Foulquier, A.S. Colinet, L. Gremillon, D. Legrand, P. Mariot, E. Peiter, E. Van Schaftingen, G. Matthijs, and P. Morsomme. (2013). Newly characterized Golgi-localized family of proteins is involved in calcium and pH homeostasis in yeast and human cells. Proc. Natl. Acad. Sci. USA 110: 6859-6864. 23569283
Deutschbauer, A., M.N. Price, K.M. Wetmore, W. Shao, J.K. Baumohl, Z. Xu, M. Nguyen, R. Tamse, R.W. Davis, and A.P. Arkin. (2011). Evidence-based annotation of gene function in Shewanella oneidensis MR-1 using genome-wide fitness profiling across 121 conditions. PLoS Genet 7: e1002385. 22125499
Dulary, E., S. Potelle, D. Legrand, and F. Foulquier. (2017). TMEM165 deficiencies in Congenital Disorders of Glycosylation type II (CDG-II): Clues and evidences for roles of the protein in Golgi functions and ion homeostasis. Tissue Cell 49: 150-156. 27401145
Foulquier, F., M. Amyere, J. Jaeken, R. Zeevaert, E. Schollen, V. Race, R. Bammens, W. Morelle, C. Rosnoblet, D. Legrand, D. Demaegd, N. Buist, D. Cheillan, N. Guffon, P. Morsomme, W. Annaert, H.H. Freeze, E. Van Schaftingen, M. Vikkula, and G. Matthijs. (2012). TMEM165 deficiency causes a congenital disorder of glycosylation. Am J Hum Genet 91: 15-26. 22683087
Hoecker, N., D. Leister, and A. Schneider. (2017). Plants contain small families of UPF0016 proteins including the PHOTOSYNTHESIS AFFECTED MUTANT71 transporter. Plant Signal Behav 0. [Epub: Ahead of Print] 28075225
Lee, J.S., M.Y. Kim, E.R. Park, Y.N. Shen, J.Y. Jeon, E.H. Cho, S.H. Park, C.J. Han, D.W. Choi, J.J. Jang, K.S. Suh, J. Hong, S.B. Kim, and K.H. Lee. (2018). TMEM165, a Golgi transmembrane protein, is a novel marker for hepatocellular carcinoma and its depletion impairs invasion activity. Oncol Rep 40: 1297-1306. 30015898
Legrand, D., M. Herbaut, Z. Durin, G. Brysbaert, M. Bardor, M.F. Lensink, and F. Foulquier. (2023). New insights into the pathogenicity of TMEM165 variants using structural modeling based on AlphaFold 2 predictions. Comput Struct Biotechnol J 21: 3424-3436. 37416081
Schneider, A., I. Steinberger, A. Herdean, C. Gandini, M. Eisenhut, S. Kurz, A. Morper, N. Hoecker, T. Rühle, M. Labs, U.I. Flügge, S. Geimer, S.B. Schmidt, S. Husted, A.P. Weber, C. Spetea, and D. Leister. (2016). The Evolutionarily Conserved Protein PHOTOSYNTHESIS AFFECTED MUTANT71 Is Required for Efficient Manganese Uptake at the Thylakoid Membrane in Arabidopsis. Plant Cell 28: 892-910. 27020959
Snyder, N.A., M.V. Palmer, T.A. Reinhardt, and K.W. Cunningham. (2019). Milk biosynthesis requires the Golgi cation exchanger TMEM165. J. Biol. Chem. 294: 3181-3191. 30622138
Stribny, J., L. Thines, A. Deschamps, P. Goffin, and P. Morsomme. (2020). The human Golgi protein TMEM165 transports calcium and manganese in yeast and bacterial cells. J. Biol. Chem. 295: 3865-3874. 32047108
Thines, L., A. Deschamps, P. Sengottaiyan, O. Savel, J. Stribny, and P. Morsomme. (2018). The yeast protein Gdt1p transports Mn ions and thereby regulates manganese homeostasis in the Golgi. J. Biol. Chem. [Epub: Ahead of Print] 29632074