View source for TMEM8B

{{Short description|Protein-coding gene in humans}}
{{Infobox gene}}
'''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.<ref name="pmid12918109">{{cite journal | vauthors = Zhang XM, Wang XY, Sheng SR, Wang JR, Li J | title = Expression of tumor related genes NGX6, NAG-7, BRD7 in gastric and colorectal cancer | journal = World Journal of Gastroenterology | volume = 9 | issue = 8 | pages = 1729–33 | date = August 2003 | pmid = 12918109 | pmc = 4611532 | doi = 10.3748/wjg.v9.i8.1729 | doi-access = free }}</ref> Aliases associated with this gene include C9orf127, NAG-5, and NGX61.<ref>[https://www.ncbi.nlm.nih.gov/protein/EAW58325.1 NCBI, Nucleotide]</ref>

== Gene ==
=== Location ===
Cytogenic location: 9p13.3<ref>{{cite web|title=NCBI Protein|url=https://www.ncbi.nlm.nih.gov/protein/EAW58325.1?report=fasta|website=NCBI|accessdate=24 April 2018}}</ref>
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 ===
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]].<ref name="ncbi.nlm.nih.gov">{{cite journal|title=Synthetic construct Homo sapiens clone ccsbBroadEn_08344 TMEM8B gene, - Nucleotide - NCBI|url=https://www.ncbi.nlm.nih.gov/nuccore/KJ898950.1|website=www.ncbi.nlm.nih.gov|date=19 March 2015 |accessdate=3 May 2018}}</ref> 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.<ref name="ncbi.nlm.nih.gov"/>

== mRNA ==
=== Splice Variants ===
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. 
 
{| class="wikitable"
|-
! style="text-align:center; | Name !! Accession Number !! Amino Acid Length !! mRNA 
|-
! style="text-align:center; | Isoform A || [https://www.ncbi.nlm.nih.gov/protein/NP_001036054.1 NP_001036055.1] || 472 || [https://www.ncbi.nlm.nih.gov/nuccore/390407646 NM_001042589.2]
|-
! style="text-align:center; | Isoform B || [https://www.ncbi.nlm.nih.gov/protein/NP_057530.2 NP_057530.2]  || 338 || [https://www.ncbi.nlm.nih.gov/nuccore/110556650 NM_016446.3]
|-
! style="text-align:center; | Isoform X1 || [https://www.ncbi.nlm.nih.gov/protein/XP_011516213.1 XP_011516213.1] || 508 || [https://www.ncbi.nlm.nih.gov/nuccore/1034670349 XM_011517911.2]
|-
! style="text-align:center; | Isoform X2 || [https://www.ncbi.nlm.nih.gov/protein/XP_011516204.1 XP_011516204.1] || 498 || [https://www.ncbi.nlm.nih.gov/nuccore/1034670340 XM_011517902.2]
|-
! style="text-align:center; | Isoform X3 || [https://www.ncbi.nlm.nih.gov/protein/XP_024303339.1 XP_024303339.1] || 482 || [https://www.ncbi.nlm.nih.gov/nuccore/1370514618 XM_024447571.1] 
|-
! style="text-align:center; | Isoform X4 || [https://www.ncbi.nlm.nih.gov/protein/XP_011516205.1 XP_011516205.1] || 399 || [https://www.ncbi.nlm.nih.gov/nuccore/1034670342 XM_011517903.2]
|-
! style="text-align:center; | Isoform X5 || [https://www.ncbi.nlm.nih.gov/protein/XP_024303338.1 XP_024303338.1] || 373 || [https://www.ncbi.nlm.nih.gov/nuccore/1370514613 XM_024447570.1]
|-
! style="text-align:center; | Isoform X6 || [https://www.ncbi.nlm.nih.gov/protein/XP_011516206.1 XP_011516206.1] || 790 || [https://www.ncbi.nlm.nih.gov/nuccore/1370514615 XM_011517904.3]
|-
! style="text-align:center; | Isoform X7 || [https://www.ncbi.nlm.nih.gov/protein/XP_011516207.1 XP_011516207.1] || 334 || [https://www.ncbi.nlm.nih.gov/nuccore/767954957 XM_011517905.1]
|-
! style="text-align:center; | Isoform X8 || [https://www.ncbi.nlm.nih.gov/protein/XP_016870294.1 XP_016870294.1] || 675 || [https://www.ncbi.nlm.nih.gov/nuccore/1034670345 XM_017014805.1]
|-
! style="text-align:center; | Isoform X9 || [https://www.ncbi.nlm.nih.gov/protein/XP_011516218.1 XP_011516218.1] || 450 || [https://www.ncbi.nlm.nih.gov/nuccore/1034670356 XM_011517916.2]
|-
! style="text-align:center; | Isoform X10 || [https://www.ncbi.nlm.nih.gov/protein/XP_016870296.1 XP_016870296.1] || 406 || [https://www.ncbi.nlm.nih.gov/nuccore/1034670357 XM_017014807.1]
|-
! style="text-align:center; | Isoform X11 || [https://www.ncbi.nlm.nih.gov/protein/XP_011516220.1 XP_011516220.1] || 398 || [https://www.ncbi.nlm.nih.gov/nuccore/1370514620 XM_011517918.3]
|}

The figure below from NCBI Gene depicts the chromosomal location of each isoform in comparison to TMEM8B.
[[File:Transcript_Isoforms_of_TMEM8B.png|thumb|center|1000px|Figure 1: Location of each isoform relative to the original TMEM8B.]]

== Protein ==
=== Protein Analysis ===
Protein analysis was completed on Isoform A.
TMEM8B isoform A is 472 amino acids long. The molecular weight is 36.8 kDa,<ref name="ebi.ac.uk">{{cite web|title=SAPS < Sequence Statistics < EMBL-EBI|url=https://www.ebi.ac.uk/Tools/seqstats/saps/|website=SAPS|accessdate=23 April 2018|language=en}}</ref> and the isoelectric point is 6.773.<ref>{{cite web|last1=Kozlowski|first1=Lukasz P.|title=IPC - ISOELECTRIC POINT CALCULATION OF PROTEINS AND PEPTIDES|url=http://isoelectric.org|website=isoelectric.org|language=en}}</ref> There are 7 [[transmembrane domains]], resulting in 52% of the protein to be within the [[plasma membrane]].<ref>{{cite web|title=TMHMM Server, v. 2.0|url=http://www.cbs.dtu.dk/services/TMHMM/|website=www.cbs.dtu.dk|language=en}}</ref> 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]].<ref name="ebi.ac.uk"/> 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.<ref name="particlesciences.com">{{cite web|title=Protein Structure: Primary, Secondary, Tertiary, Quatemary Structures|url=http://www.particlesciences.com/news/technical-briefs/2009/protein-structure.html|website=www.particlesciences.com|accessdate=3 May 2018|language=en}}</ref>

=== Secondary Structure ===
Identifying the secondary structure is helpful in further analyzing the function of this protein. [[Alpha helice]]s 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 [[Protein folding|folding region]]s, and [[random coil]]s, a class of conformations in the absence of a regular secondary structure.

[[File:Secondary_structure_TMEM8B.png|thumb|700px|center|Figure 2: Predicted secondary structure of TMEM8B, Isoform A. Predicted transmembrane domains are highlighted in green]]

=== Tertiary Structure ===
I-TASSER<ref>{{cite web|title=I-TASSER results|url=https://zhanglab.ccmb.med.umich.edu/I-TASSER/output/S392527/|website=zhanglab.ccmb.med.umich.edu|accessdate=1 May 2018}}</ref> 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.<ref name="particlesciences.com"/> Refer to the figure below to see a predicted tertiary structure.
[[File:TMEM8B_Tertiary_Structure.gif|thumb|600px|center|Figure 3: Predicted tertiary structure of TMEM8B.]]

TMEM8B highly resembles a tertiary structure that is similar to the [[Reelin|Reelin protein]], predicted by a 42% coverage and 14.79% identity.{{cn|date=January 2023}} 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.

[[File:Reelin_and_TMEM8B_MSA.png|thumb|700px|center|Figure 4: Multiple sequence alignment of the Reelin protein and TMEM8B, color coordinating with the tertiary structure.]]

== Homologogy ==
=== Orthologs ===
The orthologs of TMEM8B were sequenced in BLAST<ref>[http://blast.ncbi.nlm.nih.gov/Blast.cgi BLAST protein sequence, c9orf127]</ref> 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,<ref>Time Tree http://www.timetree.org/resources</ref> and conserved domains of the genome were found and analyzed using ClustalW.<ref>Clustal W, [http://www.genome.jp/tools-bin/clustalw Multiple Sequence Alignment]</ref>

{| class="wikitable"
|-
! style="text-align:center; | Genus Species !! Common Name !! Divergence from Humans (MYA)!! Accession Number !! Amino Acid Length !! Sequence Identity !! Sequence Similarity
|-
! style="text-align:center; | [[Homo sapiens]] || Humans || -- || [https://www.ncbi.nlm.nih.gov/protein/EAW58325.1?report=fasta EAW58325.1] || 338 || -- || --
|-
! style="text-align:center; | [[Carlito syrichta]] || Philippine tarsier || 67.1 || [https://www.ncbi.nlm.nih.gov/protein/XP_008061336.2 XP_008061336.2] || 273 || 96% || 97%
|-
! style="text-align:center; |[[West Indian manatee|Trichechus manatus latirostris]] || Florida manatee || 105 || [https://www.ncbi.nlm.nih.gov/protein/XP_004372337.1 XP_004372337.1]|| 273|| 96%|| 97%
|-
! style="text-align:center; |[[Neomonachus schauinslandi]] || Hawaiian monk seal || 96 || [https://www.ncbi.nlm.nih.gov/protein/XP_021546789.1 XP_021546789.1] || 280 || 96% || 96% 
|-
! style="text-align:center; |[[Dalmatian pelican|Pelecanus Crispus]] || Dalmatian pelican|| 312 || [https://www.ncbi.nlm.nih.gov/protein/XP_009481450.1 XP_009481450.1]|| 219|| 75% || 86%
|-
! style="text-align:center; |[[Salmo salar]] || Atlantic salmon || 435 || [https://www.ncbi.nlm.nih.gov/protein/XP_013999021.1 XP_013999021.1] || 494 || 68% || 86%
|-
! style="text-align:center; |[[Struthio camelus australis]] || Southern ostrich || 312 || [https://www.ncbi.nlm.nih.gov/protein/XP_009675834.1 XP_009675834.1]|| 283 || 70% || 81%
|-
! style="text-align:center; |[[Cariama cristata]] || Red-legged seriema || 312 ||  [https://www.ncbi.nlm.nih.gov/protein/698399778 XP_009701221.1] || 280 || 68% || 80%
|-
! style="text-align:center; |[[Egretta garzetta]] || Little egret || 312 || [https://www.ncbi.nlm.nih.gov/protein/XP_009645653.1 XP_009645653.1] || 282 || 68% || 79%
|-
! style="text-align:center; |[[Small eye golden-line fish|Sinocyclocheilus graham]] || Golden line fish || 435 || [https://www.ncbi.nlm.nih.gov/protein/XP_016091386.1 XP_016091386.1] || 295 || 62% || 76%
|-
! style="text-align:center; |[[Charadrius vociferus]]	 || Kildeer || 312 || [https://www.ncbi.nlm.nih.gov/protein/699691812 XP_009889203.1] || 420 || 63% || 75%
|-
! style="text-align:center; |[[Chrysochloris asiatica]] || Cape golden mole|| 105 || [https://www.ncbi.nlm.nih.gov/protein/XP_006863153.1 XP_006863153.1]|| 392 || 93%|| 75%
|-
! style="text-align:center; |[[Branchiostoma|Branchiostoma belcheri]] || Belcher's Lancelet|| 684 || [https://www.ncbi.nlm.nih.gov/protein/1126223746 XP_019646192.1] || 209 || 37% || 54%
|-
! style="text-align:center; |[[Xenopus laevis]] || African clawed frog || 352 || [https://www.ncbi.nlm.nih.gov/protein/XP_018123357.1 XP_018123357.1] || 480 || 65% || 50%
|-
! style="text-align:center; |[[Diachasma alloeum]] || Common house spider || 797 || [https://www.ncbi.nlm.nih.gov/protein/970879581 XP_015126938.1] || 252 || 29% || 47%
|-
! style="text-align:center; |[[Megachile rotundata]] || Alfalfa leafcutting bee || 797 ||  [https://www.ncbi.nlm.nih.gov/protein/805765715 XP_003700975.2] || 242 || 29% || 46%
|-
! style="text-align:center; |[[Strongylocentrotus purpuratus]] || Purple sea urchin || 684 || [https://www.ncbi.nlm.nih.gov/protein/780029420 XP_011666469.1] || 240 || 23% || 38%
|-
! style="text-align:center; |[[Cryptotermes brevis]] || Termite || 794 || [https://www.ncbi.nlm.nih.gov/protein/1339088644 XP_023705434.1] || 361 || 31% || 29%
|-
! style="text-align:center; |[[Exaiptasia pallida]] || Sea anemone || 824 || [https://www.ncbi.nlm.nih.gov/protein/XP_020898578.1 XP_020898578.1] || 361 || 29% ||28%
|-
! style="text-align:center; |[[Ciona intestinalis]] || Vase tunicate || 676 || [https://www.ncbi.nlm.nih.gov/protein/699238500 XP_009857467.1] || 384 || 33% || 18%
|}

=== Paralogs ===
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: [https://www.ncbi.nlm.nih.gov/protein/NP_067082.2 NP_067082.2].

=== Divergence of TMEM8B ===
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. [[File:Evolutionary_History_TMEM8B.png|thumb|center|700px|Figure 5: Evolutionary timeline for ten species including humans.]]

== Clinical significance ==
TMEM8B shows lower expression rates in [[nasopharyngeal carcinoma]]s, and expression is also down regulated in [[colorectal cancer]]s. This gene also plays a negative role in an Epidermal Growth Factor Receptor (EGFR) pathway.<ref name="pmid12918109"/> It can delay cell cycle G0-G1 progression, and thus inhibit [[cell proliferation]] in nasopharyngeal carcinoma cells.<ref name="pmid12918109"/>

Mutations with this gene can be pathogenic, and cause [[Chronic pain|chronic pain disorders]], specifically [[erythromelalgia]] symptoms.<ref name="pmid12918109"/><ref name="pmid8619474">{{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = April 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}</ref><ref name="entrez">{{cite web | work = Entrez Gene | title = C9orf127 chromosome 9 open reading frame 127| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51754| accessdate = }}</ref> 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.<ref name="rarediseases.org">{{cite web|title=Erythromelalgia - NORD (National Organization for Rare Disorders)|url=https://rarediseases.org/rare-diseases/erythromelalgia/|website=NORD (National Organization for Rare Disorders)|accessdate=2 May 2018}}</ref> Medications are available to reduce symptoms, however, there is no cure for this rare condition.<ref name="rarediseases.org"/>

== Interacting Proteins ==
Two interacting proteins were found: [[EGF-like domain|EGF protein]], and [https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATXN1L 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.<ref>{{cite journal|last1=Ma|first1=J.|title=Role of a novel EGF-like domain-containing gene NGX6 in cell adhesion modulation in nasopharyngeal carcinoma cells|url=https://academic.oup.com/carcin/article/26/2/281/2476047|journal=Carcinogenesis|volume=26|issue=2|pages=281–291|language=en|doi=10.1093/carcin/bgh312|pmid=15498789|date=16 September 2004|doi-access=free}}</ref>

ATXN1L protein has a correlation with [[neurodegenerative disorders]]. Neurodegenerative disorders are characterized by a loss of balance due to the cerebellar [[Purkinje cell|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.<ref>{{cite journal|last1=Lim|first1=Janghoo|last2=Hao|first2=Tong|last3=Shaw|first3=Chad|last4=Patel|first4=Akash J.|last5=Szabó|first5=Gábor|last6=Rual|first6=Jean-François|last7=Fisk|first7=C. Joseph|last8=Li|first8=Ning|last9=Smolyar|first9=Alex|last10=Hill|first10=David E.|last11=Barabási|first11=Albert-László|last12=Vidal|first12=Marc|last13=Zoghbi|first13=Huda Y.|title=A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration|pmid=16713569|journal=Cell|volume=125|issue=4|pages=801–814|doi=10.1016/j.cell.2006.03.032|date=19 May 2006|s2cid=13709685|doi-access=free}}</ref>

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite thesis |last1=Matsuyama |first1=Ayako | name-list-style = vanc | title = New insights into pain mechanisms through the study of genes associated with monogenic pain disorders | type = PhD Thesis | publisher = University College London | year = 2017 | url = http://discovery.ucl.ac.uk/10040307/ }}
* {{cite journal | vauthors = Wang L, Ma J, Li J, Li X, Zhang Q, Peng S, Peng C, Zhou M, Xiong W, Yang J, Zhou J, Fan S, Tan C, Yan Q, Shen S, Li G | title = NGX6 gene inhibits cell proliferation and plays a negative role in EGFR pathway in nasopharyngeal carcinoma cells | journal = Journal of Cellular Biochemistry | volume = 95 | issue = 1 | pages = 64–73 | date = May 2005 | pmid = 15723283 | doi = 10.1002/jcb.20393 | s2cid = 22108618 }}
* {{cite journal | vauthors = Peng SP, Li XL, Wang L, Ou-Yang J, Ma J, Wang LL, Liu HY, Zhou M, Tang YL, Li WS, Luo XM, Cao L, Tang K, Shen SR, Li GY | title = The role of NGX6 and its deletion mutants in the proliferation, adhesion and migration of nasopharyngeal carcinoma 5-8F cells | journal = Oncology | volume = 71 | issue = 3–4 | pages = 273–81 | year = 2006 | pmid = 17641538 | doi = 10.1159/000106073 | s2cid = 33593476 }}
* {{cite journal | vauthors = Ma J, Zhou J, Fan S, Wang L, Li X, Yan Q, Zhou M, Liu H, Zhang Q, Zhou H, Gan K, Li Z, Peng C, Xiong W, Tan C, Shen S, Yang J, Li J, Li G | title = Role of a novel EGF-like domain-containing gene NGX6 in cell adhesion modulation in nasopharyngeal carcinoma cells | journal = Carcinogenesis | volume = 26 | issue = 2 | pages = 281–91 | date = February 2005 | pmid = 15498789 | doi = 10.1093/carcin/bgh312 | doi-access = free }}
* {{cite journal | vauthors = Ma J, Li J, Zhou J, Li XL, Tang K, Zhou M, Yang JB, Yan Q, Shen SR, Hu GX, Li GY | title = Profiling genes differentially expressed in NGX6 overexpressed nasopharyngeal carcinoma cells by cDNA array | journal = Journal of Cancer Research and Clinical Oncology | volume = 128 | issue = 12 | pages = 683–90 | date = December 2002 | pmid = 12474055 | doi = 10.1007/s00432-002-0387-5 | s2cid = 21997313 }}
* {{cite journal | vauthors = Li J, Tan C, Xiang Q, Zhang X, Ma J, Wang JR, Yang J, Li W, Shen SR, Liang S, Li G | title = Proteomic detection of changes in protein synthesis induced by NGX6 transfected in human nasopharyngeal carcinoma cells | journal = Journal of Protein Chemistry | volume = 20 | issue = 3 | pages = 265–71 | date = April 2001 | pmid = 11565907 | doi = 10.1023/A:1010912311564 | s2cid = 38667111 }}
* {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = April 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
{{refend}}

== External links ==
* {{UCSC gene info|TMEM8B}}
* {{OMIM|616888|transmembrane protein 8B; TMEM8B}}
* [http://www.expasy.org ExPasy], Sibs bioinformatics analysis
* [https://www.ebi.ac.uk/Tools/psa/emboss_needle/ EMBOSS Needle Protein]