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Transmembrane protein 33 is a protein that in humans is encoded by the TMEM33 gene, also known as SHINC3 and 1600019D15Rik. Another name for TMEM33 is DB83.

Gene
This gene’s DNA location is chromosome 4 (map position 4p13) on the minus strand. Transmembrane protein 33 is ubiquitously expressed, but is particularly highly expressed in the blood.

mRNA
The mRNA transcript is 7717 base pairs long with 7 coding exons. The human coding region has the mRNA range of 366-1109 and the primary transcript has a long 3’ UTR that is over 5000 base pairs long

Characteristics
In Homo sapiens, TMEM33 protein, also known as DB83, has 9 alternative splicing patterns and 3 protein isoforms. TMEM33 is a 247 amino acid long protein with 3 transmembrane domains. The final human protein has a weight of 28 kDa and an isoelectric point of 9.88. The only known TMEM33 ortholog with four transmembrane domains is Tts1 in Schizosaccharomyces pombe. TMEM33 has a significantly high net positive charge and quantity of hydrophobic residues, particularly Leucine. TMEM33 contains a conserved domain in the protein super family UPF0121, in Homo sapiens this region spans from amino acids 1 to 246.

Post-translation modifications
Programs and experiments that analyze proteins predict various post-translational modifications of the Homo sapiens’ TMEM33. There is an experimentally determined acetylation point is at Alanine, amino acid residue 2. Phosphorylation is predicted on serine residues 197 and 198 and threonine residues 5, 127, and 193. The primary kinases that are predicted to act on TMEM33 are PKC and PKA. TMEM33 is predicted to have an O-glycosylation site at amino acid 4 and 5

Structure
The final structure of TMEM33 is unknown, but it is predicted to be composed primarily of alpha-helices and coiled domains.

Cellular localization
According to the sequence motifs of the Homo Sapiens TMEM33 it is predicted to be at the endoplasmic reticulum 48%, mitochondria 35%, and nucleus 13%. TMEM33 orthologs in mammals, aves, nematoda, and fungi were also predicted to localize to these three cellular locations: the ER first and the mitochondria second, and some orthologs a third location was predicted and it was the nucleus. Homo Sapiens TMEM33 localized with ER membrane and NE exogenously in an experiment by Urade et al 2014. The fission yeast TMEM33 ortholog, Tts1, was reported to localize to the ER and to the NE.

Homology
A TMEM33 ortholog is known to be in 148 organisms and no known paralogs exist. TMEM33 is conserved throughout animals: mammals with >95% gene similarity to humans, aves and reptiles with >90% gene similarity, amphibians and actinopterygii with >80% gene similarity, and all other invertebrate animals with >60% gene similarity. It also has very distant orthologs that have UPF0121 in fungus, yeast, and plants with a TMEM33 ortholog gene with similarity to humans of 40-50%.

Protein interactions
In humans, an affinity chromatography ran on TMEM33 showed that the protein bound to reticulon 4C, 1A, 2B,  3C, and Arl6IP1 in vitro. TMEM33 was found to interact with ubiquitin C, ubiquitin specific peptidase 19 (USP19), 40S ribosomal protein S14 (RPS14), replication protein A (RPA1, RPA2, RPA3), transitional endoplasmic reticulum ATPase (VCP), and RNA poly III initiation factor (BRF2) using affinity capture experiments with those proteins as bait. Coimmunoprecipitation experiment using two pore channel (TPC), located in the nucleus in vivo, and TMEM33 found that these two proteins bind.

Function
Urade et al 2014 found that TMEM33 exogenously suppressed reticulon 4C function, while reticulon protein is known to induce the formation of tubular structure of the ER. Therefore, TMEM33 is thought to regulate tubular ER structure. Tts1, TMEM33 ortholog in Schizosaccharomyces pombe, has been shown to be involved in dictating ER curvature as well. Using knock-out studies, Tts1 was shown to have a role in directing the spindle pole bodies and nuclear core complexes in the nuclear envelope during mitosis.