Post-GPI attachment to proteins factor 6 is an enzyme that in humans is encoded by the PGAP6 gene (previously TMEM8A). The PGAP6 protein that acts as a phospholipase A2 as part of the GPI-anchor maturation process.
Gene
Locus
The human gene TMEM8A is found on chromosome 16 at the band 16p13.3.
The span of this gene on chromosome 16 spans from base pair 420,773 to 437,113 making this gene 16,340 base pairs in length. This gene is found on the minus strand of the chromosome. There are no known isoforms.
Aliases
TMEM8A is also known as Transmembrane protein 8A, Transmembrane Protein 6, Five-Span Transmembrane Protein M83, TMEM6, TMEM8, Transmembrane protein 8 and M83.
Homology
Paralogs
There are two paralogs for TMEM8A found in humans, C9orf127 and TMEM8C. Both of these paralogs are found on Chromosome 9.
Orthologs
The ortholog space of TMEM8A is fairly narrow, with the majority of orthologs found in mammals and in particular primates with only a few exceptions. Genus and species Common name Class Accession Percent identity Pan troglodytes Chimpanzee Mammalia XP_510709 99% Pongo abelii Orangutan Mammalia XP_002825960 97% Macaca mulatta Rhesus monkey Mammalia XP_001118461 93% Callithrix jacchus Marmoset Mammalia ABZ80344 93% Rattus norvegicus Rat Mammalia XP_001070176 43% Bos taurus Cow Mammalia NP_001092377 69% Ailuropoda melanoleuca Panda Mammalia EFB17134 78% Canis familiaris Dog Mammalia XP_003639163 74% Equus caballus Horse Mammalia XP_001915452 78% Felis catus Cat Mammalia XP_003999121 75% Monodelphis domestica Opossum Mammalia XP_001378110 44% Ornithorhynchus anatinus Platypus Mammalia XP_001512398 50% Gallus gallus Chicken Aves XP_003643243 56% Anolis carolinensis Lizard Reptilia XP_003230229 53% Xenopus tropicalis Frog Amphibia XP_002943473 43% Takifugo rubripes Pufferfish Actinopterygii XP_003975883 44% Danio rerio Zebrafish Acrinoptergii XP_00139040 44% Strongylacentrotus putputatus Sea urchin Echinoidea XP_795452 29% Drosophila melanogaster Fruit fly Insecta NP_651350 36%
Protein
Primary sequence
The gene encodes a protein also called TMEM8A. This protein in 771 amino acids in length but has been shown to have a signal peptide from amino acid 1 to 34; the mature form of the protein is only 737 amino acids in length. The precursor form with signal peptide intact has a molecular weight of 84.780 kilodaltons and the mature form with the signal peptide cleaved has a molecular weight of 81.624 kilodaltons TMEM8A has an isoelectric point of the mature form of pI=7.3.
Domains and motifs
TMEM8A is a transmembrane protein with five transmembrane domains, making it one of only three proteins found in the human body with five domains; the other two are CD47 and AC133. The protein also contains an EGF-like domain, which is a sequence of about thirty to forty amino-acid residues, found in the sequence of epidermal growth factor (EGF), that has been shown to be present in a more or less conserved form in a large number of other, mostly animal, proteins. The functional significance of EGF domains in what appear to be unrelated proteins is not yet clear. However, a common feature is that these repeats are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. The EGF domain includes six cysteine residues which have been shown (in EGF) to be involved in disulphide bonds. The main structure is a two-stranded beta-sheet followed by a loop to a short C-terminal two-stranded sheet. Subdomains between the conserved cysteines vary in length.
Post-translational modifications
The protein has been shown to undergo glycosylation post-translationally at amino acids 144, 407, and 431.Prediction of N-glycosylation sites in human proteins. R. Gupta, E. Jung and S. Brunak. In preparation, 2004. There are also three disulfide bonds between amino acid 498 and 508, 502 and 521, and 523 and 532. These disulfide bonds are all characteristic of proteins with an EGF-like domain.
Secondary Structure
Expression
Expression
TMEM8A is found to be expressed ubiquitously throughout the human body; however, it has been shown to be downregulated during CD4+ and CD8+ T-cell activation.
Transcript variants
There are three natural transcript variants of TMEM8A. One is located at amino acid 136 where a threonine is swapped for an alanine. Another is present at amino acid 310 where an isoleucine is swapped for a valine and one at amino acid 567 where an arginine is swapped for a tryptophan. None of these variants result in a change of expression nor any loss/gain of function mutations.
Interacting proteins
Transcription factors
There are many predicted transcription factor binding sites in the TMEM8A promoter. Below is a table of the best possibilities, which have high confidence values, evolutionary conservation, and/or multiple possible binding sites in the promoter.
Transcription factor Start End Strand Sequence Insulimoma associated factors 1 13 + Plemorphic adenoma gene 1 3 25 + Hypermethylated in cancer 1 11 23 - Zinc finger with KRAB and SCAN domains 3 15 37 - Glial cells missing homolog 1 18 32 + Basic krueppel-like factor (KLF3) 19 35 + Zinc finger protein Spalt-2, sal-like 2, p150(sal2) 23 33 + MYC-associated zinc finger protein related transcription factor 23 35 + Myeloid zinc finger protein MZF1 27 37 + Hypermethylated in cancer 1 29 41 - Yin and Yang 1 activator sites 38 60 - Y box binding protein 1, has a preference for binding ssDNA 41 53 + Glial cells missing homolog 1 54 68 - Wilms Tumor Suppressor 71 84 + Runt-related transcription factor 2 / CBFA1 (core-binding factor, runt domain, alpha subunit 1) 73 87 + GLI-Kruppel family member GLI3 74 88 - Zinc finger with KRAB and SCAN domains 3 87 103 -
Interactions
TMEM8A has been shown to interact with the following proteins ALPL NDUFS5 NME4 MACF1 G5 ENSG00000234651 ENSG00000237431 ENSG00000237495
References