TMEM63A

Transmembrane protein 63A is a is_associated_with::protein that in humans is encoded by the TMEM63A is_associated_with::gene. The mature human protein is approximately 92.1 kilodaltons (kDa), with a relatively high conservation of mass in orthologs. The protein contains eleven is_associated_with::transmembrane domains and is inserted into the membrane of the is_associated_with::lysosome. BioGPS analysis for TMEM63A in humans shows that the gene is ubiquitously expressed, with the highest levels of expression found in is_associated_with::T-cells and is_associated_with::dendritic cells.

Overview
TMEM63A is located on the negative DNA strand of is_associated_with::chromosome 1 at location 1q42.12, spanning is_associated_with::base pairs 226,033,237 to 226,070,069. Aliases include KIAA0489 and KIAA0792. The human gene product is a 4,469 is_associated_with::base pair is_associated_with::mRNA with 25 predicted is_associated_with::exons. There are 9 predicted splice isoforms of the gene, three of which are protein coding. Promoter analysis was carried out using El Dorado through the is_associated_with::Genomatix software page. The predicted promoter region spans 971 is_associated_with::base pairs, from 226,070,920 to 226,069,950 on the negative strand of is_associated_with::chromosome 1.

Gene neighborhood
TMEM63A is located adjacent to the is_associated_with::EPHX1 gene on the positive sense strand of DNA on is_associated_with::chromosome 1, as well as the LEFTY1 gene on the negative sense strand. Other genes in the same area on is_associated_with::chromosome 1 include is_associated_with::SRP9 and LEFTY3 on the positive strand, and MIR6741 and is_associated_with::PYCR2 on the negative strand.

Expression
TMEM63 is ubiquitously expressed throughout the human body at varying levels, occurring with the highest relative prevalence in CD 8+ T cells and CD 4+ T cells. Moderate relative levels of expression are also observed throughout the brain, particularly in the is_associated_with::occipital lobe, is_associated_with::parietal lobe, and is_associated_with::pancreas. Analysis of TMEM63A expression in the mouse using BioGPS revealed more variable expression patterns, with the highest expression being seen in the is_associated_with::stomach and is_associated_with::large intestine. Using the El Dorado program from is_associated_with::Genomatix, is_associated_with::transcription factor regulation was predicted, which found that ‘’TMEM63A’’ is highly regulated by is_associated_with::E2F is_associated_with::cell cycle regulators and is_associated_with::EGR1, a factor believed to be a is_associated_with::tumor suppressor gene with expression in the is_associated_with::brain. The 3’ UTR is predicted to be bound by the regulatory element miR-9/9ab.

Properties and characteristics
The mature form of the human TMEM63A protein has 807 is_associated_with::amino acid residues with an is_associated_with::isoelectric point of 6.925. This is fairly conserved across orthologs. A is_associated_with::BLAST alignment revealed that the protein contains three domains: RSN1_TM and two domains of unknown function (DUF4463 and DUF221). RSN1_TM is predicted to be involved in is_associated_with::Golgi vesicle transport and is_associated_with::exocytosis. DUF4463 is is_associated_with::cytosolic and distantly homologous to is_associated_with::RNA-binding proteins. This domain can be used to determine the orientation of the protein in the is_associated_with::membrane, with the is_associated_with::N-terminus of the protein being within the is_associated_with::lysosome and the is_associated_with::C-terminus located in the is_associated_with::cytosol.

Post-translational modification has been determined both experimentally and using bioinformatic analysis. There are two likely sites of is_associated_with::glycosylation on the protein: N38 and N450. These were predicted using the NetNGlyc program from is_associated_with::ExPASy and the TMEM63A amino acid sequence, as well as the inferred orientation of the protein in the membrane. There are three likely sites of is_associated_with::phosphorylation on the protein: S85, S98, and S735, which were predicted using the NetPhos program.

The protein has three is_associated_with::isoforms. The mature protein is designated isoform CRA. The other two isoforms are X1 and X2, which are 630 amino acid residues and 468 amino acid residues long, respectively. Isoform X1 is missing the is_associated_with::N-terminus of the mature protein, while isoform 2 is missing the is_associated_with::C-terminus.

Interactions
Using text-based information, TMEM63A is thought to potentially interact with six other proteins: is_associated_with::EEF1D, is_associated_with::FAM163B, is_associated_with::CPNE9, is_associated_with::TMEM90A, is_associated_with::STAC2, is_associated_with::HEATR3, and is_associated_with::WDR67.

Function
The function of TMEM63A is not known, although one study found it was in a region likely regulated by is_associated_with::mir-200a, linked to epithelial homeostasis. Another found it to be in a quantitative trait locus linked to is_associated_with::haloperidol-induced is_associated_with::catalepsy.

Paralogs
TMEM63A has two paralogs: TMEM63B, which is located at 6p21.1, and TMEM63C, which is located at C14orf171. Alignment between them shows that TMEM63C is more closely related to TMEM63B than TMEM63A. A BLAST alignment showed homology of TMEM63A and TMEM63B to proteins as distantly related as plants, while TMEM63C was homologous only as distantly as in is_associated_with::drosophila. This indicates that TMEM63C likely diverged from the two early in is_associated_with::invertebrates.

Ortholog space
TMEM63A has a large ortholog space, with homologs present in organisms as distantly related as plants.