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C13orf46

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C13orf46
Identifiers
AliasesC13orf46, uncharacterized LOC100507747, chromosome 13 open reading frame 46
External IDsHomoloGene: 139853; GeneCards: C13orf46; OMA:C13orf46 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

100507747

n/a

Ensembl

ENSG00000283302
ENSG00000283199

n/a

UniProt

n
a

n/a

RefSeq (mRNA)

NM_001365455

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)Chr 13: 113.95 – 113.97 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Chromosome 13 Open Reading Frame 46 is a protein which in humans is encoded by the C13orf46 gene.[3] In humans, C13orf46 is ubiquitously expressed at low levels in tissues, including the lungs, stomach, prostate, spleen, and thymus. This gene encodes eight alternatively spliced mRNA transcript, which produce five different protein isoforms.

Gene

An alternative name for C13orf46 is LOC100507747.[4] C13orf46 spans 47,563 base pairs, contains 11 exons, and is on the minus strand of chromosome 13 at 13q34.[5][6]

Graphical representation of the location of the human C13orf46 gene.[3] The red arrow pointing to the left represents the span of the gene C13orf46.

Gene neighbors

The neighboring genes around C13orf46 include LINC00454, LINC00452, SWINGN, RASA3, and LOC124903221.[7]

LINC00454 and LINC00452 (Long Intergenic NonProtein Coding RNA 454 & 452) are both long non-coding RNAs (lncRNA) that regulate epigenetic gene expression, chromatin remodeling, and levels of gene transcription and translation.[7][8][9] Both LINC00454 and LINC00452 expression are restricted to the testis. LINC00454 has been associated with Factor X Deficiency while LINC00452 has been found to promote ovarian carcinogenesis.[10][11]

SWINGN (SWI/SNF Complex Interacting GAS6 Enhancer Non-Coding RNA) is also a lncRNA that neighbors C13orf46.[12] SWINGN regulates the activation of the GAS6 (Growth Arrest Specific 6) oncogene, by interacting with matrix associated and actin dependent regulators of chromatin.[13]

The RASA3 (RAS p21 Protein Activator 3) gene encodes the Ras GTPase activating protein. This protein binds inositol 1,3,4,5-tetrakisphosphate to stimulate the activity of Ras p21 and negatively regulates the Ras signaling pathway.[14] RASA3 is most highly expressed in fat, lymph nodes, and the spleen. The encoded protein is localized to the cell membrane.

mRNA

Eight different transcript variants have been identified for C13orf46.[7] These transcript variants are alternatively spliced to include variations of 11 different exons. Depending on the different transcript variant that is translated, 5 different possible protein isoforms are encoded by C13orf46. The most common protein product encoded by C13orf46 is isoform 1, which is 212 amino acids long.[15]

Table of Variants and Exons[3]
Transcript Variant mRNA Length (nt) Protein Isoform Protein Length (aa) Molecular Weight (kDA) Exon 1 (bp) Exon 2 (bp) Exon 3 (bp) Exon 4 (bp) Exon 5 (bp) Exon 6 (bp) Exon 7 (bp) Exon 8 (bp) Exon 9 (bp) Exon 10 (bp) Exon 11 (bp)
C13orf46 transcript variant 1 3786 C13orf46 protein isoform 1 212 23.4 269 52 166 48 48 68 3135
C13orf46 transcript variant X1 26461 C13orf46 protein isoform X1 624 66.7 3269 252 1920 21020
C13orf46 transcript variant X2 26389 C13orf46 protein isoform X1 624 66.7 3269 252 20903 1965
C13orf46 transcript variant X3 25642 C13orf46 protein isoform X1 624 66.7 3269 252 19745 2376
C13orf46 transcript variant X4 26573 C13orf46 protein isoform X2 587 62.8 3269 252 23052
C13orf46 transcript variant X5 29437 C13orf46 protein isoform X3 212 23.4 269 52 166 48 48 68 3337 25449
C13orf46 transcript variant X6 961 C13orf46 protein isoform X4 192 21.1 269 52 166 48 48 68 310
C13orf46 transcript variant X7 833 C13orf46 protein isoform X5 175 18.9 269 52 166 48 246 52

Protein

The primary protein isoform of the C13orf46 gene consists of 212 amino acids.[15][16] The longest encoded isoform, known as C13orf46 protein isoform X1, is 624 amino acids long.[17] Other protein isoforms encoded by the C13orf46 gene are similar to either of these two versions of the C13orf46 protein. Varying forms of the primary 212 amino acid protein is encoded by transcript variants 1, X5, X6, and X7. Variations of the longest C13orf46 protein isoform are encoded by transcript variants X1, X2, X3, and X4.

Protein isoform 1

Properties and composition

C13orf46 Isoform 1 has a theoretical isoelectric point of 4.84 and a predicted molecular weight of 23.4 kDA.[18] Higher relative amounts of glutamic acid (15.1%) and aspartic acid (7.5%) are found within this isoform, while the amino acids phenylalanine (0.9%) and threonine (0.5%) are found to be less abundant within the protein composition.[19] C13orf46 Isoform 1 also has a glutamic acid rich region where multiple glutamic acid and lysine doublets are present, some of which occur side by side. A total of 14 multiplets are found within the protein overall, 12 of which are charged.[19] C13orf46 Isoform 1 is not predicted to contain any charge clusters, hydrophobic segments, or transmembrane segments.

Structure

iTASSER predicted tertiary structure of C13orf46 Isoform 1.[20]

C13orf46 Protein Isoform 1 is predicted to consist of 7 alpha helices and 2 beta strands in addition to regions of random free coils.[21][20]

Domains and motifs

C13orf46 Isoform 1 has two identified disordered regions spanning between amino acid residues 1 through 148 and 168 to 190.[22] In addition, C13orf46 Isoform 1 has a glutamic acid rich region spanning along amino acid residues 109 to 191.[19]

Regulation and post translational modifications

C13orf46 Isoform 1 is predicted to undergo several post-translational modifications such as phosphorylation,[23][24][25] O-GlcNAcylation,[24] mucin type GalNAc O-glycosylation,[24] palmitoylation,[26][27] and sumoylation.[28] PKA, PKC, CKII, PKG, GSK3, cdc2, RSK, and ATM are kinases that are predicted to bind and phosphorylate the human C13orf46 Isoform 1. There is also one predicted phosphoprotein-binding phosphosite on the protein.[29]

Schematic illustration of C13orf46 Isoform 1 annotated with relevant predicted post translational modifications.[30] Red pentagons represent predicted relevant O-glycosylation sites, yellow spheres represent significant phosphorylation sites, and pink trapezoids represent predicted sumoylation sites. The predicted significant site of palmitoylation is represented by a purple diamond, while the phosphoprotein-binding phosphosite is depicted with a blue hexagon. A glutamic acid rich region within C13orf46 Isoform 1 is shown as a blue domain between amino acids 109 to 191
C13orf46 Isoform 1 annotated tertiary structure prediction from iTASSER with highest confidence score.[31][32] Glutamic acid within the glutamic acid rich region is shown as spheres. The magenta highlights the N-terminal UBR box recognition site for E3 ubiquitin ligases. The green highlights show selected phosphorylation sites that are most conserved and relevant significant predictions based on scores and cross referencing predictions between site tools. The sections highlighted in yellow indicate locations within the protein where O-linked glycosylation may occur. These sections were selected based on comparisons between site prediction tools, score values, and comparisons with orthologs.

Protein isoform X1

Properties

C13orf46 Isoform X1 has a theoretical isoelectric point of 9.33 and a predicted molecular weight of 66.7 kDA.[18] C13orf46 Isoform X1 protein contains much higher relative amounts of serine (18.4%) and leucine (18.8%) compared to other human proteins and also has high amounts of proline (14.4%).[19] Roughly equal amounts of serine and leucine are found within the protein. C13orf46 Isoform X1 protein is also composed of lower than usual amounts of glutamic acid (1.3%), phenylalanine (0.3%), and lysine (0.5%) and also has low amounts of valine (2.4%).[19] Asparagine is not found within the C13orf46 Isoform X1 protein. Within this isoform, 100 amino acid multiplets are found, 5 of which are charged. No charge clusters, hydrophobic segments or transmembrane domains are predicted within the protein.[19]

Structure

C13orf46 Isoform X1 is predicted to consist of a combination of alpha helices, beta sheets, and free random coil regions.[33] There are 22 predicted alpha helices and 18 predicted beta sheets within the predicted structure of C13orf46 Isoform X1.

iTASSER predicted tertiary structure of C13orf46 Isoform X1[33]
Logo of 26 repeats within C13orf46 Isoform X1[34]

C13orf46 Isoform X1 contains a series of 26 repeats, which vary in sequence structure and length.[19][35] Out of the 26 identified repeat sequences, 14 sequences consisted of 20 amino acids, while 5 of the repeats consisted of 21 amino acids, 3 repeats consisted of 22 amino acids, and 4 repeats were 23 amino acids long.[36] Each repeat sequence beings with either the amino acid methionine, isoleucine, or leucine. The main sequence structure of the amino acids within the 26 repeats is MLLLSTGCSSSPPDAPPLHQ.[34] An alignment of the 26 repeats indicate that the most conserved part of the repeat sequence occurs in the middle of the sequences with a triplet of the amino acid serine.[36][37]

Logo the 14 repeats out of all 26 repeats within C13orf46 Isoform X1 consisting of only 20 amino acids, illuminating the main internal structure of the 26 repeats.[34]

Domains and motifs

C13orf46 Isoform X1 has a predicted a dimerization domain between amino acids residues 69 to 87.[38]

Regulation and post translational modification

C13orf46 Isoform X1 is predicted to undergo several post-translational modifications such as phosphorylation,[23][24][25] O-GlcNAcylation,[24] mucin type GalNAc O-glycosylation,[24] palmitoylation,[26][27] and sumoylation.[28] The human C13orf46 Isoform X1 protein also has 11 predicted PPBD-specific binding phosphosites.[29] The most conserved phosphorylation sites occur on the third serine of 23 out of 26 repeats. PKC, PKG, PKA, p38MAPK, GSK3, DNAPK, CKI, cdk5, CKII, and cdc2 are kinases predicted to bind and phosphorylate the human C13orf46 Isoform X1 protein.[24] Predicted phosphorylated sites are also predicted to be sites where O-glycosylation can occur.[24]

Schematic diagram of predicted significant post translational modifications of C13orf46 Isoform X1.[39] The 26 repeats are shown in alternating color. Predicted phosphorylation sites of CKII are represented by yellow spheres. Three repeats that do not have a predicted to be phosphosite by CKII but are predicted O-GlcNAcylated and/or GalNAc O-glycosylated are depicted as pentagons. Two sites that are only predicted to be O-GlcNAcylated are shown in light pink, while the site predicted to have the potential to be both O-GlcNAcylated and GalNAc O-glycosylated is illustrated in red. A predicted dimerization domain is highlighted by a pink box. One significant s-palmitoylation site predicted on the protein is represented by a purple diamond.
Annotated tertiary structure of C13orf46 depicting charge and hydrophobic regions within the protein. The serine's that are predicted to be phosphorylated by CKII are illustrated in green. The dimerization domain predicted between amino acids 69 to 87 are depicted as spheres. The 26 repeats are highlighted and shown in alternating color of blue and purple.

Protein interactions

C13orf46 protein isoform X1 has several predicted S-phase cyclin binding sites, in addition to MAPK and p38 interacting motifs.[40]

Expression

RNA sequencing shows the expression of C13orf46 is most observed in the lungs, prostate, pancreas, and stomach at intermediate levels.[7][41] C13orf46 also has lower expression levels in the bone marrow, spleen, thyroid, lymph node, gall bladder, and thymus.

Cellular localization

C13orf46 Isoform 1 is predicted to be mostly localized within the nucleus.[42][24] This protein isoform may also be localized on the cell membrane.[24] C13orf46 Isoform X1 is predicted to be mostly localized within the nucleus[42][24] or cytoplasm.[24]

Homology

Orthologs

The C13orf46 gene has orthologs to the human C13orf46 isoform 1 protein and C13orf46 isoform X1 protein, found within primates, mammals, birds, reptiles, fish, and invertebrates.[43]

Isoform 1

Orthologs to the human C13orf46 isoform 1 protein are only known to be found in primates and mammals, suggesting that this part of the C13orf46 gene encoding the C13orf46 isoform 1 protein appeared around 99 million years ago.[43]

Unrooted phylogenetic tree of C13orf46 isoform 1 evolutionary history.[44] Circles indicate species groups of like taxons. The red circle highlights primates, the yellow circle indicates carnivores, and the purple circle indicates rodents.
Table of Orthologs to Human Protein C13orf46 Isoform 1[43]
Genus and Species Common Name Taxonomic Group Median Date of Divergence (mya) Accession # Sequence Length (aa) Sequence Identity (%) Sequence Similarity (%)
Homo sapiens Human Primates 0 NP_001352384.1 212 100.0% 100.0%
Pan paniscus Bonobo Primates 6.4 XP_034792262.1 212 98.1% 98.1%
Gorilla gorilla gorilla Western Lowland Gorilla Primates 8.6 XP_030857272.1 212 95.3% 98.1%
Papio anubis Olive Baboon Primates 28.9 XP_021785522.1 212 88.7% 92.5%
Cercocebus atys Sooty Mangabey Primates 28.9 XP_011913555.1 192 87.3% 91.0%
Macaca mulatta Rhesus Macaque Primates 28.9 XP_014977020.1 192 79.2% 82.5%
Ursus arctos Brown Bear Carnivora 87 XP_048071403.1 222 59.2% 71.3%
Callorhinus ursinus Northern Fur Seal Carnivora 87 XP_025730354.1 184 57.5% 65.6%
Lontra canadensis Northern River Otter Carnivora 87 XP_032736869.1 232 46.4% 53.6%
Odobenus rosmarus divergens Pacific Walrus Carnivora 87 XP_004412327.1 310 36.4% 41.7%
Loxodonta africana African Bush Elephant Proboscidea 87 XP_010591994.1 214 62.6% 73.4%
Choloepus didactylus Two-Toed Sloth Pilosa 87 XP_037662557.1 214 60.7% 73.8%
Orycteropus afer afer Aardvark Tubulidentata 87 XP_007940592.1 214 60.0% 69.3%
Castor canadensis North American Beaver Rodentia 87 XP_020020073.1 217 59.6% 72.0%
Pteropus giganteus Indian Flying Fox Chiroptera 94 XP_039734682.1 213 67.6% 76.5%
Eptesicus fuscus Big Brown Bat Chiroptera 94 XP_028004567.1 214 65.9% 75.2%
Trichechus manatus latirostris Antillean Manatee Sirenia 94 XP_023589319.1 214 63.1% 74.3%
Balaenoptera musculus Blue Whale Cetacea 94 XP_036687016.1 207 57.3% 69.0%
Urocitellus parryii Arctic Ground Squirrel Rodentia 94 XP_026237314.1 216 61.9% 72.0%
Sciurus carolinensis Eastern Gray Squirrel Rodentia 94 XP_047409299.1 238 55.6% 66.1%
Ictidomys tridecemlineatus Thirteen-Lined Ground Squirrel Rodentia 94 XP_013221671.2 276 49.3% 57.6%
Chinchilla lanigera Long-Tailed Chinchilla Rodentia 99 XP_005373979.1 217 55.5% 66.4%
Arvicola amphibius European Water Vole Rodentia 99 XP_038185081.1 237 53.1% 65.1%
Mesocricetus auratus Golden Hamster Rodentia 99 XP_005082676.1 237 51.0% 61.8%
Arvicanthis niloticus African Grass Rat Rodentia 99 XP_034376776.1 241 50.0% 61.9%

Isoform X1

Predicted orthologs to the human C13orf46 isoform X1 protein are found in primates, mammals, birds, reptiles, fish, and as far as back as invertebrates of the bacterial phylum Legionella.[43]

Table of Predicted Orthologs to Human Protein C13orf46 Isoform X1[43]
Genus and Species Common Name Taxonomic Group Median Date of Divergence (mya) Accession # Sequence Length (aa) Sequence Identity (%) Sequence Similarity (%)
Homo sapiens Human Primates 0 XP_047285937.1 624 100.0% 100.0%
Pan troglodytes Chimpanzee Primates 6.4 XP_024209271.1 720 54.9% 61.0%
Microtus ochrogaster Prairie Vole Rodentia 87 KAH0512811.1 936 10.3% 15.8%
Phoca vitulina European Harbour Seal Carnivora 94 XP_032285971.1 510 18.8% 30.1%
Orcinus orca Killer Whale Cetacea 94 XP_049556886.1 348 14.2% 19.3%
Myotis davidii Whiskered Bat Chiroptera 94 ELK34143.1 530 26.1% 33.6%
Phasianus colchicus Ring-Necked Pheasant Galliformes 319 XP_031464934.1 499 23.2% 33.5%
Corvus hawaiiensis Hawaiian Crow Passeriformes 319 XP_048182949.1 316 17.3% 23.4%
Hirundo rustica Barn Swallow Passeriformes 319 XP_039927228.1 1185 10.0% 14.9%
Pelodiscus sinensis Chinese Soft-Shelled Turtle Testudines 319 XP_025042872.1 554 17.3% 26.4%
Rana temporaria Grass Frog Anura 353 XP_040201915.1 1147 12.9% 19.7%
Bufo bufo Common Toad Anura 353 XP_040296088.1 259 12.3% 19.7%
Lithobates catesbeianus American Bullfrog Anura 353 PIO00716.1 245 12.0% 18.5%
Larimichthys crocea Large Yellow Croaker Perciformes 431 KAE8277666.1 478 28.9% 37.9%
Coregonus clupeaformis Lake Whitefish Salmoniformes 431 XP_041725148.2 609 27.0% 26.0%
Austrofundulus limnaeus Killifish Cyprinodontiformes 431 XP_013856594.1 244 22.7% 25.4%
Oncorhynchus tshawytscha Chinook Blackmouth Salmon Salmoniformes 431 XP_042158955.1 714 23.5% 26.2%
Salmo salar Atlantic Salmon Salmoniformes 431 XP_045562793.1 324 19.9% 20.9%
Prochilodus magdalenae Columbian Freshwater Fish Characiformes 431 KAI4891011.1 388 18.6% 25.4%
Oncorhynchus mykiss Rainbow Trout Salmoniformes 431 XP_036845983.1 332 18.5% 27.3%
Chiloscyllium punctatum Brownbanded Bamboo Shark Orectolobiformes 464 GCC17506.1 625 26.7% 26.8%
Biomphalaria glabrata Freshwater Snail Basommatophora 694 KAI8768938.1 308 14.4% 18.9%
Bulinus truncatus Freshwater Snail Basommatophora 694 KAH9489149.1 879 10.3% 30.7%
Owenia fusiformis Bristle Worm Canalipalpata 694 CAH1787814.1 224 14.3% 15.2%
Legionella fallonii Legionella Legionellales 3036 WP_045095679.1 695 15.2% 30.7%

Paralogs

Human C13orf46 isoform X1 protein has one predicted paralog among mucins, specifically mucin-1.[43] Mucins play a role in creating protective mucus barriers on epithelial tissues.[45] The MUC1 gene is located on chromosome 1 at 1q22, contains 11 exons, and has 22 different isoforms.[46] Mucins are highly O-glycosylated and contain tandem repeat domains abundant with proline, serine, and threonine.[47] Surrounding the repeat domains are cysteine rich regions. Mucin genes do not always share a common ancestry, are prone to convergent evolution, and are grouped based on their functionality instead of common evolutionary history.[48]

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