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TMEM8B

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TMEM8B
Identifiers
AliasesTMEM8B, C9orf127, NAG-5, NGX6, NAG5, transmembrane protein 8B
External IDsOMIM: 616888; MGI: 2441680; HomoloGene: 72894; GeneCards: TMEM8B; OMA:TMEM8B - orthologs
Orthologs
SpeciesHumanMouse
Entrez

51754

242409

Ensembl

ENSG00000137103

ENSMUSG00000078716

UniProt

A6NDV4

B1AWJ5

RefSeq (mRNA)

NM_001085508
NM_001355718
NM_001368840
NM_001368841
NM_001368842

RefSeq (protein)

NP_001078977
NP_001342647
NP_001355769
NP_001355770
NP_001355771

Location (UCSC)Chr 9: 35.81 – 35.87 MbChr 4: 43.67 – 43.69 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Transmembrane protein 8B is a protein that in humans is encoded by the TMEM8B gene. It encodes for a transmembrane protein that is 338 amino acids long, and is located on human chromosome 9.[5] Aliases associated with this gene include C9orf127, NAG-5, and NGX61.[6]

Gene

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Location

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Cytogenic location: 9p13.3[7] Located on chromosome 9 in the human genome. It starts at base pair 35,814,451, and ends at 35,865,518, and contains 19 exons. There are 13 transcript variants that are protein encoding, and the longest transcript variant is 790 amino acids long.

Expression

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Using information from NCBI's EST Abundance Profile page on TMEM8B, expression levels vary in 32 different human tissues. The highest levels of expression can be found in the brain, ovaries, prostate, placenta, and the pancreas.[8] Expression levels are down regulated in some cancerous tissue, specifically nasopharyngeal and colorectal carcinomas. TMEM8B is expressed in all stages of development, including fetal stages, as low levels of expression are present in the fetal liver, brain, and thymus.[8]

mRNA

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Splice Variants

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TMEM8B has 13 known mRNA splice variants in humans: Refer to the table below. All 13 variants are protein encoding, and all contain 19 exons.

Name Accession Number Amino Acid Length mRNA
Isoform A NP_001036055.1 472 NM_001042589.2
Isoform B NP_057530.2 338 NM_016446.3
Isoform X1 XP_011516213.1 508 XM_011517911.2
Isoform X2 XP_011516204.1 498 XM_011517902.2
Isoform X3 XP_024303339.1 482 XM_024447571.1
Isoform X4 XP_011516205.1 399 XM_011517903.2
Isoform X5 XP_024303338.1 373 XM_024447570.1
Isoform X6 XP_011516206.1 790 XM_011517904.3
Isoform X7 XP_011516207.1 334 XM_011517905.1
Isoform X8 XP_016870294.1 675 XM_017014805.1
Isoform X9 XP_011516218.1 450 XM_011517916.2
Isoform X10 XP_016870296.1 406 XM_017014807.1
Isoform X11 XP_011516220.1 398 XM_011517918.3

The figure below from NCBI Gene depicts the chromosomal location of each isoform in comparison to TMEM8B.

Figure 1: Location of each isoform relative to the original TMEM8B.

Protein

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Protein Analysis

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Protein analysis was completed on Isoform A. TMEM8B isoform A is 472 amino acids long. The molecular weight is 36.8 kDa,[9] and the isoelectric point is 6.773.[10] There are 7 transmembrane domains, resulting in 52% of the protein to be within the plasma membrane.[11] The C-charge> N-charge, and therefore the C-terminal end is on the inside. Transmembrane domains are conserved in most orthologs, including all mammals. Relative to other proteins, TMEM8B has higher than normal levels of K, Lysine, and L, Leucine.[9] There are three repeating leucine-rich regions within conserved domains of TMEM8B, all 4 amino acids long. Leucine rich regions can result in hydrophobic interactions within themselves.[12]

Secondary Structure

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Identifying the secondary structure is helpful in further analyzing the function of this protein. Alpha helices are the strongest indicators of transmembrane regions, as the helical structure can satisfy all backbone hydrogen-bonds internally. This is why the secondary structure of this protein is practical, as many of the alpha helices lie in the predicted transmembrane regions. Other key structures identified in this protein include extended strands, which are hypothesized to be important folding regions, and random coils, a class of conformations in the absence of a regular secondary structure.

Figure 2: Predicted secondary structure of TMEM8B, Isoform A. Predicted transmembrane domains are highlighted in green

Tertiary Structure

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I-TASSER[13] predicted the 3D tertiary structure of TMEM8B, with strategic folding of the alpha helices and beta sheets. Although there are no high scoring hydrophobic segments of TMEM8B, that would usually be hidden within the interior of the 3D structure, the high amounts of Leuceine (L) amino acids in this protein creates hydrophobic interactions with itself, and these areas are predicted to be buried on the inside of the structure.[12] Refer to the figure below to see a predicted tertiary structure.

Figure 3: Predicted tertiary structure of TMEM8B.

TMEM8B highly resembles a tertiary structure that is similar to the Reelin protein, predicted by a 42% coverage and 14.79% identity.[citation needed] The Reelin protein has no transmembrane domains, and is mostly found in the cerebral cortex and the hippocampus, where it plays important roles in the control of neuronal migration and formation of cellular layers during brain development.

Figure 4: Multiple sequence alignment of the Reelin protein and TMEM8B, color coordinating with the tertiary structure.

Homologogy

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Orthologs

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The orthologs of TMEM8B were sequenced in BLAST[14] and 20 various orthologs were picked. The orthologs are all multicellular organisms, and vary through mammals, rodents, birds, fish, amphibians, echinoderms, chordates, insects, and cnidarians. Refer to the table below. Time tree was a program that was used to find the evolutionary branching shown in MYA,[15] and conserved domains of the genome were found and analyzed using ClustalW.[16]

Genus Species Common Name Divergence from Humans (MYA) Accession Number Amino Acid Length Sequence Identity Sequence Similarity
Homo sapiens Humans -- EAW58325.1 338 -- --
Carlito syrichta Philippine tarsier 67.1 XP_008061336.2 273 96% 97%
Trichechus manatus latirostris Florida manatee 105 XP_004372337.1 273 96% 97%
Neomonachus schauinslandi Hawaiian monk seal 96 XP_021546789.1 280 96% 96%
Pelecanus Crispus Dalmatian pelican 312 XP_009481450.1 219 75% 86%
Salmo salar Atlantic salmon 435 XP_013999021.1 494 68% 86%
Struthio camelus australis Southern ostrich 312 XP_009675834.1 283 70% 81%
Cariama cristata Red-legged seriema 312 XP_009701221.1 280 68% 80%
Egretta garzetta Little egret 312 XP_009645653.1 282 68% 79%
Sinocyclocheilus graham Golden line fish 435 XP_016091386.1 295 62% 76%
Charadrius vociferus Kildeer 312 XP_009889203.1 420 63% 75%
Chrysochloris asiatica Cape golden mole 105 XP_006863153.1 392 93% 75%
Branchiostoma belcheri Belcher's Lancelet 684 XP_019646192.1 209 37% 54%
Xenopus laevis African clawed frog 352 XP_018123357.1 480 65% 50%
Diachasma alloeum Common house spider 797 XP_015126938.1 252 29% 47%
Megachile rotundata Alfalfa leafcutting bee 797 XP_003700975.2 242 29% 46%
Strongylocentrotus purpuratus Purple sea urchin 684 XP_011666469.1 240 23% 38%
Cryptotermes brevis Termite 794 XP_023705434.1 361 31% 29%
Exaiptasia pallida Sea anemone 824 XP_020898578.1 361 29% 28%
Ciona intestinalis Vase tunicate 676 XP_009857467.1 384 33% 18%

Paralogs

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One human paralog was found when this protein was sequenced in BLAST. It is 416 amino acids long, with 40% sequence identity, and 45% sequence similarity. Accision number for this protein is: NP_067082.2.

Divergence of TMEM8B

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In an evolutionary comparison of TMEM8B, one species from each group (ex. Mammals, birds, fish) was plotted to avoid overabundance of information on one graph. Also plotted the comparison of the quickly diverging cytochrome C, and slowly diverging fibrinogen. TMEM8B shows divergence somewhere in-between these two proteins.

Figure 5: Evolutionary timeline for ten species including humans.

Clinical significance

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TMEM8B shows lower expression rates in nasopharyngeal carcinomas, and expression is also down regulated in colorectal cancers. This gene also plays a negative role in an Epidermal Growth Factor Receptor (EGFR) pathway.[5] It can delay cell cycle G0-G1 progression, and thus inhibit cell proliferation in nasopharyngeal carcinoma cells.[5]

Mutations with this gene can be pathogenic, and cause chronic pain disorders, specifically erythromelalgia symptoms.[5][17][18] Erythromelalgia is a rare condition that affects the extremities (hands and feet), and is characterized by intense, burning pain, severe redness, and increased skin temperature.[19] Medications are available to reduce symptoms, however, there is no cure for this rare condition.[19]

Interacting Proteins

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Two interacting proteins were found: EGF protein, and ATXN1L protein.

EGF plays a role in cell adhesion in nasopharyngeal carcinomas (TMEM8B also plays a role in these carcinomas). This protein is expressed on the cell surface as a glycoprotein, and ectopic induction of EGF can impair NPC cell migration and improve cell adhesion and gap junctional intercellular communication.[20]

ATXN1L protein has a correlation with neurodegenerative disorders. Neurodegenerative disorders are characterized by a loss of balance due to the cerebellar Purkinje degeneration. Ataxia-causing proteins share interacting partners, a subset of which has been found to modify neurodegeneration in animal models. Interactome provides a tool for understanding pathogenic mechanisms common for neurodegenerative disorders.[21]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000137103 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000078716 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d Zhang XM, Wang XY, Sheng SR, Wang JR, Li J (August 2003). "Expression of tumor related genes NGX6, NAG-7, BRD7 in gastric and colorectal cancer". World Journal of Gastroenterology. 9 (8): 1729–33. doi:10.3748/wjg.v9.i8.1729. PMC 4611532. PMID 12918109.
  6. ^ NCBI, Nucleotide
  7. ^ "NCBI Protein". NCBI. Retrieved 24 April 2018.
  8. ^ a b "Synthetic construct Homo sapiens clone ccsbBroadEn_08344 TMEM8B gene, - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. 19 March 2015. Retrieved 3 May 2018.
  9. ^ a b "SAPS < Sequence Statistics < EMBL-EBI". SAPS. Retrieved 23 April 2018.
  10. ^ Kozlowski, Lukasz P. "IPC - ISOELECTRIC POINT CALCULATION OF PROTEINS AND PEPTIDES". isoelectric.org.
  11. ^ "TMHMM Server, v. 2.0". www.cbs.dtu.dk.
  12. ^ a b "Protein Structure: Primary, Secondary, Tertiary, Quatemary Structures". www.particlesciences.com. Retrieved 3 May 2018.
  13. ^ "I-TASSER results". zhanglab.ccmb.med.umich.edu. Retrieved 1 May 2018.
  14. ^ BLAST protein sequence, c9orf127
  15. ^ Time Tree http://www.timetree.org/resources
  16. ^ Clustal W, Multiple Sequence Alignment
  17. ^ Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
  18. ^ "C9orf127 chromosome 9 open reading frame 127". Entrez Gene.
  19. ^ a b "Erythromelalgia - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2 May 2018.
  20. ^ Ma, J. (16 September 2004). "Role of a novel EGF-like domain-containing gene NGX6 in cell adhesion modulation in nasopharyngeal carcinoma cells". Carcinogenesis. 26 (2): 281–291. doi:10.1093/carcin/bgh312. PMID 15498789.
  21. ^ Lim, Janghoo; Hao, Tong; Shaw, Chad; Patel, Akash J.; Szabó, Gábor; Rual, Jean-François; Fisk, C. Joseph; Li, Ning; Smolyar, Alex; Hill, David E.; Barabási, Albert-László; Vidal, Marc; Zoghbi, Huda Y. (19 May 2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–814. doi:10.1016/j.cell.2006.03.032. PMID 16713569. S2CID 13709685.

Further reading

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