TMEM33

Last updated March 29, 2024

Transmembrane protein 33 is a protein that in humans, is encoded by the TMEM33 gene, also known as SHINC3.^[1] Another name for the TMEM33 protein is DB83.

Gene

Location of TMEM33 on human chromosome 4 TMEM33 location on Human Chromosome 4.png — Location of TMEM33 on human chromosome 4

In humans, this gene’s DNA location is the short arm of chromosome 4, loci position: 4p13.^[3] The genomic range is 41937502-41956213, spanning 18.7 kb, on the positive strand.^[3] Transmembrane protein 33 is ubiquitously expressed, but is particularly highly expressed in the blood, lymph nodes, bone, and adipose tissue.^[4]^[5]

Promoter

A promoter sequence upstream of TMEM33 is GXP_4428588. This 1069 base pair promoter sequence spans 41936535-41937603 on human chromosome 4.^[6] The promoter sequence overlaps with the 5' untranslated region, first coding exon, and first intron of the TMEM33 gene. Many different transcription factors are known to bind to this region.^[6] The most likely to bind transcription factors are expressed most in connective tissue (i.e. blood, adipose tissue, and bone), the immune system, and nervous system.^[6]

mRNA

Eleven different mRNA transcript variants of TMEM33 exist, 9 alternatively spliced variants and 2 unspliced forms.^[7] 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. These three variants only vary in 3' UTR length.^[7] 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.^[8]

Protein

Characteristics

In Homo sapiens, TMEM33 protein has 5 different coding mRNA variants that encode 3 different protein isoforms.^[10] The largest and most common human TMEM33 protein is 247 amino acid long protein with 3 transmembrane domains.^[11] The only known TMEM33 ortholog with four transmembrane domains is Tts1 in Schizosaccharomyces pombe.^[12] The human protein has a predicted molecular weight of 28 kDa^[13] and an isoelectric point of 9.88.^[14] 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.^[15] TMEM33 contains a conserved domain in the protein super family UPF0121, in Homo sapiens this region spans from amino acids 1 to 246.^[11]

Post-translation modifications

Programs and experiments that analyze proteins predict various post-translational modifications of TMEM33. There is an experimentally determined acetylation point is at alanine, amino acid residue 2 in humans.^[11] Human TMEM33 has phosphorylation predicted on serine residues 197 and 198 and threonine residues 5, 127, and 193.^[16] The primary kinases that are predicted to act on TMEM33 are Protein kinase C (PKC) and PKA.^[17] TMEM33 is predicted to have an O-glycosylation site at human amino acid residues 4 and 5^[18]

Structure

The exact secondary structure of TMEM33 is unknown, but it is predicted to be composed primarily of alpha-helices and coiled domains.^[19] 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 (ER) 48%, mitochondria 35%, and nucleus 13%.^[12] 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.^[12] Homo Sapiens TMEM33 localized with ER membrane and NE exogenously.^[20] The fission yeast TMEM33 ortholog, Tts1, was reported to localize to the ER and to the NE (nuclear envelope).^[21]

Homology

A TMEM33 ortholog is known to be in over 150 organisms and no known paralogs exist.^[1]

TMEM33 is conserved throughout all animals, similarity to human TMEM33 is >80% for all vertebrates and >60% for all invertebrates.^[22] TMEM33 has very distant orthologs that have UPF0121 in fungus, yeast, and plants.^[22]

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.^[20] 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 polymerase III initiation factor (BRF2) using affinity capture experiments with those proteins as bait.^[23] Coimmunoprecipitation experiment found two-pore channel (TPC), an ion channel, and TMEM33 bind.^[24]

Function

TMEM33 localizes to the endoplasmic reticulum (ER) membrane and the nuclear envelope, and therefore must function in these regions.^[20] TMEM33 exogenously suppresses reticulon 4C function, which is a protein that induces the formation of the tubular structure of the ER.^[20] 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.^[21] 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.^[21]

Related Research Articles

Reticulons are a group of evolutionary conservative proteins residing predominantly in endoplasmic reticulum, primarily playing a role in promoting membrane curvature. In addition, reticulons may play a role in nuclear pore complex formation, vesicle formation, and other processes yet to be defined. They have also been linked to oligodendrocyte roles in inhibition of neurite outgrowth. Some studies link RTNs with Alzheimer's disease and amyotrophic lateral sclerosis.

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TMEM143 is a protein that in humans is encoded by TMEM143 gene. TMEM143, a dual-pass protein, is predicted to reside in the mitochondria and high expression has been found in both human skeletal muscle and the heart. Interaction with other proteins indicate that TMEM143 could potentially play a role in tumor suppression/expression and cancer regulation.

TMEM156 is a gene that encodes the transmembrane protein 156 (TMEM156) in Homo sapiens. It has the clone name of FLJ23235.

Uncharacterized protein C12orf60 is a protein that in humans is encoded by the C12orf60 gene. The gene is also known as LOC144608 or MGC47869. The protein lacks transmembrane domains and helices, but it is rich in alpha-helices. It is predicted to localize in the nucleus.

Transmembrane and coiled-coil domains 4, TMCO4, is a protein in humans that is encoded by the TMCO4 gene. Currently, its function is not well defined. It is transmembrane protein that is predicted to cross the endoplasmic reticulum membrane three times. TMCO4 interacts with other proteins known to play a role in cancer development, hinting at a possible role in the disease of cancer.

Transmembrane protein 44 is a protein that in humans is encoded by the TMEM44 gene.

TMEM44 is a protein that in humans is encoded by the TMEM44 gene. DKFZp686O18124 is a synonym of TMEM44.

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<span class="mw-page-title-main">Small integral membrane protein 14</span>

Small integral membrane protein 14, also known as SMIM14 or C4orf34, is a protein encoded on chromosome 4 of the human genome by the SMIM14 gene. SMIM14 has at least 298 orthologs mainly found in jawed vertebrates and no paralogs. SMIM14 is classified as a type I transmembrane protein. While this protein is not well understood by the scientific community, the transmembrane domain of SMIM14 may be involved in ER retention.

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TMEM275 is a protein that in humans is encoded by the TMEM275 gene. TMEM275 has two, highly-conserved, helical trans-membrane regions. It is predicted to reside within the plasma membrane or the endoplasmic reticulum's membrane.

SMIM19, also known as Small Integral Membrane Protein 19, encodes the SMIM19 protein. SMIM19 is a confirmed single-pass transmembrane protein passing from outside to inside, 5' to 3' respectively. SMIM19 has ubiquitously high to medium expression with among varied tissues or organs. The validated function of SMIM19 remains under review because of on sub-cellular localization uncertainty. However, all linked proteins research to interact with SMIM19 are associated with the endoplasmic reticulum (ER), presuming SMIM19 ER association

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Transmembrane protein 212 is a protein that in humans is encoded by the TMEM212 gene. The protein consists of five transmembrane domains and localizes in the plasma membrane and endoplasmic reticulum. TMEM212 has orthologs in vertebrates but not invertebrates. TMEM212 has been associated with sporadic Parkinson's disease, facial processing, and adiposity in African Americans.

KIAA2013, also known as Q8IYS2 or MGC33867, is a single-pass transmembrane protein encoded by the KIAA2013 gene in humans. The complete function of KIAA2013 has not yet been fully elucidated.

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References

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1 2 3 "PSORTII Server". Archived from the original on 2021-09-06. Retrieved 2015-04-22.
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↑ "NetOGlyc 4.0" . Retrieved 2015-04-12.
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1 2 3 4 "Identification and Characterization of TMEM33 as a Reticulon-binding Protein" (PDF). Retrieved 2015-02-22.
1 2 3 Zhang, Dan; Oliferenko, Snezhana (2014). "Tts1, the fission yeast homologue of the TMEM33 family, functions in NE remodeling during mitosis". Molecular Biology of the Cell. 25 (19): 2970–2983. doi:10.1091/mbc.e13-12-0729. PMC 4230586 . PMID 25103238.
1 2 "NCBI: BLAST" . Retrieved 2015-03-22.
↑ "Biogrid protein interactions with TMEM33" . Retrieved 2015-04-17.
↑ "The Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation" . Retrieved 2015-02-22.