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

Gene

In humans, this gene’s DNA location is the short arm of chromosome 4, loci position: 4p13. The genomic range is 41937502-41956213, spanning 18.7 kb, on the positive strand. Transmembrane protein 33 is

ubiquitously Omnipresence or ubiquity is the property of being present anywhere and everywhere. The term omnipresence is most often used in a religious context as an attribute of a deity or supreme being, while the term ubiquity is generally used to describe ...

expressed, but is particularly highly expressed in the blood, lymph nodes, bone, and adipose tissue.

Promoter

A promoter sequence upstream of TMEM33 is GXP_4428588. This 1069 base pair promoter sequence spans 41936535-41937603 on human chromosome 4. The promoter sequence overlaps with the 5' untranslated region, first coding exon, and first

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

of the TMEM33 gene. Many different transcription factors are known to bind to this region. The most likely to bind transcription factors are expressed most in

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

(i.e. blood, adipose tissue, and bone), the immune system, and nervous system.

mRNA

Eleven different mRNA transcript variants of TMEM33 exist, 9 alternatively spliced variants and 2 unspliced forms. Only 5 variants (a, b, c, d, and e) encode proteins. Transcripts a, b, and c encode the same 247 amino acid long protein because each have the same 7 typical coding

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

. These three variants only vary in 3' UTR length. Transcripts a, b, and c have a 744 base pair long coding range and a particularly long 3’ UTR that is 6000 base pairs long.

Protein

Characteristics

In Homo sapiens, TMEM33 protein has 5 different coding mRNA variants that encode 3 different protein isoforms. The largest and most common human TMEM33 protein is 247 amino acid long protein with 3 transmembrane domains. The only known TMEM33 ortholog with four transmembrane domains is Tts1 in Schizosaccharomyces pombe. The human protein has a predicted molecular weight of 28 kDa and an isoelectric point of 9.88. TMEM33 has a significantly high net positive charge and quantity of hydrophobic residues. In particular, leucine that makes up 17.8% of the human TMEM33 protein. 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 TMEM33. There is an experimentally determined

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...

point is at alanine, amino acid residue 2 in humans. Human TMEM33 has

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

predicted on

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

residues 197 and 198 and

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...

residues 5, 127, and 193. The primary kinases that are predicted to act on TMEM33 are

Protein kinase C In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

(PKC) and

PKA PKA may refer to: * Professionally known as: ** Pen name ** Stage persona * p''K''a, the symbol for the acid dissociation constant at logarithmic scale * Protein kinase A, a class of cAMP-dependent enzymes * Pi Kappa Alpha, the North-American so ...

. TMEM33 is predicted to have an O-glycosylation site at human amino acid residues 4 and 5

Structure

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

Cellular localization

According to the sequence motifs of the Homo Sapiens, TMEM33 it is predicted to be at the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER) 48%,

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

35%, and nucleus 13%. TMEM33 orthologs in vertebrates, invertebrates, 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. The fission yeast TMEM33 ortholog, Tts1, was reported to localize to the ER and to the NE (

nuclear envelope The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material. The nuclear envelope consists of two lipid bilayer membrane ...

Homology

A TMEM33 ortholog is known to be in over 150 organisms and no known paralogs exist. TMEM33 is conserved throughout all animals, similarity to human TMEM33 is >80% for all vertebrates and >60% for all invertebrates. TMEM33 has very distant orthologs that have UPF0121 in fungus, yeast, and plants.

Protein Interactions

Using human proteins, 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 40S ribosomal protein S14 is a protein that in humans is encoded by the ''RPS14'' gene. Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 ...

), replication protein A (RPA1, RPA2, RPA3), transitional endoplasmic reticulum ATPase (VCP), and RNA polymerase III initiation factor ( BRF2) using affinity capture experiments with those proteins as bait.

Coimmunoprecipitation Immunoprecipitation (IP) is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a samp ...

experiment found two-pore channel (TPC), an ion channel, and TMEM33 bind.

Function

TMEM33 localizes to the endoplasmic reticulum (ER) membrane and the nuclear envelope, and therefore must function in these regions. TMEM33 exogenously suppresses reticulon 4C function, which is a protein that induces the formation of the tubular structure of the ER. Therefore, TMEM33 is thought to regulate tubular ER structure through modulation of reticulon activity. Tts1, TMEM33 ortholog in S. pombe, has been found to be involved in dictating ER curvature as well. In the nucleus, knock-out studies indicate Tts1 has a role in directing the spindle pole bodies and nuclear core complexes in the nuclear envelope during mitosis.