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C15orf62

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C15orf62
Identifiers
AliasesC15orf62, chromosome 15 open reading frame 62
External IDsMGI: 3651144; HomoloGene: 85847; GeneCards: C15orf62; OMA:C15orf62 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

643338

623781

Ensembl

ENSG00000188277

ENSMUSG00000055926

UniProt

A8K5M9

Q8CE97

RefSeq (mRNA)

NM_001130448

NM_001039223

RefSeq (protein)

NP_001123920

NP_001034312

Location (UCSC)Chr 15: 40.77 – 40.77 MbChr 2: 119 – 119.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

C15orf62 is a protein which in humans is encoded by the C15orf62 gene.[5] The protein displays high levels of expression in the esophagus and skin of human tissue.[6] C15orf62 is a regulatory protein involved in mitochondrial function and cytoskeletal organization, playing roles in ribosomal biogenesis, Rho protein signal transduction, and protein turnover through ubiquitination.[7] It connects mitochondrial activity to cell structure, signaling, and biogenesis through its unique amino acid composition and post-translational modifications.

Gene

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Gene family of human C15orf62 from the National Center for Biotechnology Information (NCBI Gene).

The gene is also known as chromosome 15 open reading frame 62.[5] The human C15orf62 gene spans 2,470 base pairs, and is oriented on the plus strand of cytogenetic band 15q15.1. The C15orf62 gene contains a single exon and transcribes a protein-coding mRNA that encodes a 175 amino acid protein.[7]

Protein

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Human C15orf62 encodes a single protein, with just a singular isoform.[5] The protein has a molecular weight of 19.7 kD and an isoelectric point (pI) of 8.66.[8] C15orf62 has a high abundance of arginine and significantly lower levels of valine.[9] A dot-matrix analysis of C15orf62 revealed one prominent internal amino acid repeat, "RL-R-SS."[10]

The protein contains eight motifs; an amidation site, an N-glycosylation site, cAMP- and a cGMP-dependent protein kinase phosphorylation sites, a casein kinase II phosphorylation site, an N-myristoylation site, a protein kinase C phosphorylation site, and a protein prenyltransferases alpha subunit repeat profile, and a domain of unknown function (DUF2437).[11]

C15orf62 contains a histidine kinase sensor, TorS sensor domain, functioning in response to diverse signals and mediating signal transduction across the plasma membrane in all prokaryotes and certain eukaryotes.[12]

Gene Level Regulation

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C15orf62 RNA expression patterns reveal tissue enhanced in the esophagus and skin. Ubiquitously moderate to low expression can be seen across other human tissues.[6] Microarray data from normal tissue expression profiling of 24 human C15orf62 tissue samples revealed expression is moderate to low in most parts of the body based on findings in the National Center for Biotechnology Information, Gene Expression Omnibus (NCBIGeo).[13] In-situ hybridization of the human brain from Allen Brain Atlas indicated that C15orf62 exhibits the highest expression levels throughout the myelencephalon. In contrast, expression in the cerebral cortex is exceptionally lower.[14]

Immunohistochemical staining of the human esophagus displayed moderate cytoplasmic positivity of C15orf62 in squamous epithelial cells.[6]

Transcript Level Regulation

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Annotated conceptual translation of the human C15orf62 gene, highlighting prominent features generated using Bioline Six-Frame.[15] Note that C15orf62 consists of a single exon.

The gene contains an active enhancer region proceeding the coding sequence (CDS) and three histone H3 lysine 4 mono-methylation (H3K4me1) human embryonic stem cell (hESC) sites marking poised or active enhancers throughout C15orf62. H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation.[16]

Protein Level Regulation

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The C15orf62 gene is localized to the mitochondria with a confidence level of 78.3%.[17]

The following post-translation modification tools revealed notable findings: YinoYang indicated several O-beta GlcNAc attachment signals. Phosphosite detected six phosphorylation sites.[18] NetPhos - 3.1 indicated several phosphorylation sites.[19] NetAcet - 1.0 displayed an acetylation at one sequence, position 3 T, and NetNGlyc displayed one signal at position 11, NASF.[20][21]

PSORT II detected two nuclear localization signals highly conserved in orthologs (RPRR and PRRLRRQ).[17]

PSORT II also identified a cleavage site for a mitochondrial pre-sequence in the protein, using the Gavel tool. The cleavage occurs after residue 38, at the sequence RRQ|SS.[17] This is consistent with the R-2 motif (arginine at position -2), which is a common feature of mitochondrial targeting sequences cleaved by mitochondrial processing peptidases. This suggests that the protein is transported to the mitochondria, where its pre-sequence is removed to generate the mature form.

Homology

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Orthologs

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An unrooted phylogenetic tree depicting orthologs of human C15orf62 created using NGPhylogeny.fr.[22] The colored circles indicate the classes used to group organisms: blue for mammals, brown for aves, green for reptiles, red for amphibians, and purple for chondrichthyes.

The C15orf62 gene has many orthologs but is found exclusively in vertebrates. The most divergent orthologs are within the class Chondrichthyes (cartilaginous fish), which diverged approximately 462 million years ago (MYA).[23][24]

This gene is present across mammals, birds, reptiles, amphibians, and cartilaginous fish. The most evolutionarily distant ortholog of human C15orf62 is found in the smalltooth sawfish (Pristis pectinata), which exhibits 20.7% sequence identity and 32% sequence similarity to the human gene. This pattern implies that while C15orf62 is relatively well-conserved within the vertebrate lineage, its function may have diverged or adapted significantly across different classes, particularly in more evolutionarily distant groups such as amphibians and cartilaginous fish.[24]

Table: Orthologs of Human C15orf62
C15orf62 Genus/Species Common Name Taxonomic Group (Order) Median Date of Divergence (MYA) Accession Number Sequence Length (aa) Sequence Identity (%) Sequence Similarity (%) Sequence Divergence (%) Corrected Divergence (%)
Mammalia Homo sapiens Human Primates 0 NP_001123920.1 175 100 100 (N/A) (N/A)
Aves Anas platyrhynchos Mallard Anseriformes 319 XP_012963840.1 176 42.0 55.9 58.0 86.8
Struthio camelus australis South African Ostrich Struthioniformes 319 KFV84981.1 182 39.9 56.9 60.1 91.9
Merops nubicus Northern Carmine Bee-eater Coraciiformes 319 XP_008942659.1 176 38.8 55.9 61.2 94.7
Taeniopygia guttata Zebra Finch Passeriformes 319 XP_012429774.1 171 38.6 53.8 61.4 95.2
Gallus gallus Red Junglefowl Galliformes 319 XP_001232488.1 176 38.3 55.3 61.7 96.0
Reptillia Chelonoidis abingdonii Pinta Island Tortoise Testudines 319 XP_032624925.1 169 41.0 61.2 59.0 89.2
Pelodiscus sinensis Chinese Softshell Turtle Testudines 319 XP_014431805.1 169 42.0 61.3 38.7 86.8
Caretta caretta Loggerhead sea turtle Testudines 319 XP_048708641.1 169 40.4 62.4 59.6 90.6
Crocodylus porosus Saltwater Crocodile Crocodylia 319 XP_019407196.1 179 38.3 56.3 61.7 96.0
Zootoca vivipara Viviparous lizard Squamata 319 XP_034967260.1 180 36.3 51.8 63.7 101.3
Notechis scutatus Eastern Tigersnake Squamata 319 XP_026520364.1 175 36.0 55.4 64.0 102.2
Crotalus tigris Tiger Rattlesnake Squamata 319 XP_039179775.1 176 35.9 52.1 64.1 102.4
Protobothrops mucrosquamatus Brown-Spotted Pit Viper Squamata 319 XP_015670018.1 176 35.1 52.7 64.9 104.7
Gekko japonicus Schlegel's Japanese Gecko Squamata 319 XP_015270831.1 177 34.7 53.4 65.3 105.9
Thamnophis sirtalis Common Gartersnake Squamata 319 XP_013916913.1 176 34.0 52.7 66.0 107.9
Amphibia Microcaecilia unicolor Tiny Cayenne Caecilian Caecilians 352 XP_030069876.1 181 28.5 39.8 71.5 125.6
Rhinatrema bivittatum Two-lined Caecilian Caecilians 352 XP_029454446.1 205 26.3 39.3 73.5 133.6
Chondrichthyes Heterodontus francisci Horn Shark Heterodontiformes 462 XP_067895762.1 195 23.2 34.8 76.8 146.1
Scyliorhinus canicula Small-spotted Catshark Carcharhiniformes 462 XP_038639367.1 196 22.5 30.9 69.1 149.2
Pristis pectinata Smalltooth Sawfish Rhinopristiformes 462 XP_051900207.1 245 20.7 32.0 68.0 157.5
Strict ortholog alignment of the C15orf62 gene in Homo sapiens, generated using the Clustal Omega tool.[25] Amino acids with similar chemical properties are color-coded, with highly conserved sequences marked by asterisks (*), moderately conserved sequences by colons (:), and less conserved sequences by periods (.). Highly repeated conserved regions are highlighted with red boxes for emphasis.

The above table displays orthologs of human C15orf62 in organisms of various classes. The orthologs have been grouped according to the sequence identity of the human protein. Mammalia (100%), aves (38%-42%), reptilia (34%-41%), amphibia (26%-29%), and chondrichthyes (20%-23%). NCBI's Basic Local Alignment Search Tool (BLAST), TimeTree, and EMBOSS Needle were utilized to collect the above data.[26][23][27]

Distant ortholog alignment of the C15orf62 gene in Homo sapiens generated using Clustal Omega.[25] Amino acids with similar chemical properties are color-coded, with highly conserved regions marked by asterisks (*), moderately conserved regions by colons (:), and lower conservation by periods (.). Highly repeated conserved regions are highlighted with red boxes, while the disordered region of the protein is enclosed in black boxes.

Paralogs

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Human C15orf62 multiple sequence alignment key.

C15orf62 has no paralogs as can be determined by a BLAST run on NCBI Protein using the human C15orf62 sequence against the non-redundant database.[26] The lack of significant results indicated that the gene has no duplications within the species.

Biochemistry

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C15orf62 plays a key role in both mitochondrial function and cytoskeletal organization. It is involved in Rho protein signal transduction, regulating cytoskeletal dynamics and cell shape through interactions with small GTPases.[28] In the mitochondria, it is directly involved in ribosomal biogenesis, supported by its interactions with mitochondrial ribosomal proteins such as MRPS18A and GFM2.[29][28] The protein contains a mitochondrial targeting sequence that is cleaved at residue 38, confirming its role in mitochondrial processes.[29] Additionally, C15orf62 interacts with NEDD4, an E3 ubiquitin ligase, indicating its involvement in protein turnover through ubiquitination.[30] With its unique amino acid composition and multiple post-translational modification sites, C15orf62 acts as a regulatory protein connecting mitochondrial activity to processes like biogenesis, signaling, and cell structure.

Interacting Proteins

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Human neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), an E3 ubiquitin-protein ligase involved in regulating various cellular processes such as signal transduction, cell differentiation, and apoptosis, interacts with human C15orf62, as determined by phage display. This interaction suggests a role for C15orf62 in protein turnover through ubiquitination.[30][31]

Additionally, C15orf62 has an interactome involving several mitochondrial proteins, including C15orf61, C3orf33, MRPS18A, MRPL53, GFM2, MTER4, and DNAJC11, indicating its involvement in mitochondrial ribosome biogenesis and other mitochondrial functions. Interactions with proteins like DNAJC17, DNAJC4, and ZFYVE19, localized in other cellular compartments, suggest C15orf62 may also be involved in processes beyond the mitochondria, such as protein folding and cell division.[17]

Clinical Significance

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C15orf62 has been identified as a methylene-driven gene in thyroid cancer. Hypomethylation causes gene over-expression, and hypermethylation leads to low gene expression, both key factors in tumor development.[32] C15orf62 has also been linked to breast cancer susceptibility performing a role in mitochondrial ribosomal biogenesis, assembling mitochondrial ribosomes.[33]

Alternative tertiary structure of the human C15orf62 protein, shown as a space-filling model with conserved regions highlighted based on identified conserved sites in the conceptual translation. The structure was generated by AlphaFold and visualized using NCBI iCn3D.[34][35]

An expression profile for diabetes ORFs was detected in C15orf62 found in liver secretion. This indicates the capability of enhancing diagnostic markers for diabetes types 1 and 2. A distinct expression profile for C15orf62 was detected in blood.[36]

Identified single nucleotide polymorphisms (SNPs) in human C15orf62 include T75N, P83A, and S148fs.[37]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000188277 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055926 – 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 "C15orf62 chromosome 15 open reading frame 62 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-09-20.
  6. ^ a b c "C15orf62 protein expression summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2024-12-13.
  7. ^ a b Database, GeneCards Human Gene. "C15orf62 Gene - GeneCards | CO062 Protein | CO062 Antibody". www.genecards.org. Archived from the original on 2023-01-16. Retrieved 2024-12-13.
  8. ^ "Expasy - Compute pI/Mw tool". web.expasy.org. Retrieved 2024-12-13.
  9. ^ "SAPS". www.ebi.ac.uk. Retrieved 2024-12-13.
  10. ^ "Dotlet JS". dotlet.vital-it.ch. Retrieved 2024-12-13.
  11. ^ "Motif Scan". myhits.sib.swiss. Retrieved 2024-12-13.
  12. ^ Moore, Jason O.; Hendrickson, Wayne A. (2009-09-09). "Structural Analysis of Sensor Domains from the TMAO-Responsive Histidine Kinase Receptor TorS". Structure. 17 (9): 1195–1204. doi:10.1016/j.str.2009.07.015. ISSN 0969-2126. PMID 19748340.
  13. ^ "Home - GEO - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-12-13.
  14. ^ "Microarray Data :: Allen Brain Atlas: Human Brain". human.brain-map.org. Retrieved 2024-12-13.
  15. ^ "Six-Frame Translation". www.bioline.com. Retrieved 2024-12-13.
  16. ^ Kubo, Naoki; Chen, Poshen B.; Hu, Rong; Ye, Zhen; Sasaki, Hiroyuki; Ren, Bing (2024-05-02). "H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation". Molecular Cell. 84 (9): 1742–1752.e5. doi:10.1016/j.molcel.2024.02.030. ISSN 1097-2765. PMC 11069443. PMID 38513661.
  17. ^ a b c d "PSORT II Prediction". psort.hgc.jp. Retrieved 2024-12-05.
  18. ^ "Gm14137 (human)". www.phosphosite.org. Retrieved 2024-12-13.
  19. ^ "NetPhos 3.1 - DTU Health Tech - Bioinformatic Services". services.healthtech.dtu.dk. Retrieved 2024-12-13.
  20. ^ "NetAcet 1.0 - DTU Health Tech - Bioinformatic Services". services.healthtech.dtu.dk. Retrieved 2024-12-13.
  21. ^ "NetNGlyc 1.0 - DTU Health Tech - Bioinformatic Services". services.healthtech.dtu.dk. Retrieved 2024-12-13.
  22. ^ "NGPhylogeny.fr". ngphylogeny.fr. Retrieved 2024-12-13.
  23. ^ a b "TimeTree :: The Timescale of Life". timetree.org. Retrieved 2024-12-13.
  24. ^ a b "C15orf62 orthologs". NCBI. Retrieved 2024-12-13.
  25. ^ a b "EMBL-EBI". www.ebi.ac.uk. Retrieved 2024-12-13.
  26. ^ a b "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2024-12-13.
  27. ^ "EMBL-EBI". www.ebi.ac.uk. Retrieved 2024-12-13.
  28. ^ a b "UniProt". www.uniprot.org. Retrieved 2024-12-13.
  29. ^ a b "PSORT II Prediction". psort.hgc.jp. Retrieved 2024-12-13.
  30. ^ a b "BioGRID | Database of Protein, Chemical, and Genetic Interactions". thebiogrid.org. Retrieved 2024-12-13.
  31. ^ Di Gregorio, Jacopo; Appignani, Martina; Flati, Vincenzo (2023-12-06). "Role of the Mitochondrial E3 Ubiquitin Ligases as Possible Therapeutic Targets in Cancer Therapy". International Journal of Molecular Sciences. 24 (24): 17176. doi:10.3390/ijms242417176. ISSN 1422-0067. PMC 10743160. PMID 38139010.
  32. ^ Chen, Zhiwei; Liu, Xiaoli; Liu, Fangfang; Zhang, Guolie; Tu, Haijian; Lin, Wei; Lin, Haifeng (2021-08-29). "Identification of 4-methylation driven genes based prognostic signature in thyroid cancer: an integrative analysis based on the methylmix algorithm". Aging (Albany NY). 13 (16): 20164–20178. doi:10.18632/aging.203338. ISSN 1945-4589. PMC 8436924. PMID 34456184.
  33. ^ Podder, Bristy Rani; Kheya, Ilora Shabnam; Elias, Sabrina Moriom (2024-02-01). "Breast cancer risk SNPs and associated expression QTLs focusing Bangladeshi population: An in silico analysis". Human Gene. 39: 201270. doi:10.1016/j.humgen.2024.201270. ISSN 2773-0441.
  34. ^ "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2024-12-13.
  35. ^ "iCn3D: Web-based 3D Structure Viewer". www.ncbi.nlm.nih.gov. Retrieved 2024-12-13.
  36. ^ Narayanan, Ramaswamy (2014-07-19). ""Diabetes Associated Genes from the Dark Matter of the Human Proteome"". MOJ Proteomics & Bioinformatics. 1 (4). doi:10.15406/mojpb.2014.01.00020. ISSN 2374-6920. Archived from the original on 2024-07-15.
  37. ^ "Home - SNP - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-12-13.

Further Reading

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  • Bartolák-Suki, Erzsébet; Imsirovic, Jasmin; Nishibori, Yuichiro; Krishnan, Ramaswamy; Suki, Béla (2017-08-21). "Regulation of Mitochondrial Structure and Dynamics by the Cytoskeleton and Mechanical Factors". International Journal of Molecular Sciences. 18 (8): 1812. doi:10.3390/ijms18081812. ISSN 1422-0067. PMC 5578198. PMID 28825689.
  • Di Gregorio, Jacopo; Appignani, Martina; Flati, Vincenzo (2023-12-06). "Role of the Mitochondrial E3 Ubiquitin Ligases as Possible Therapeutic Targets in Cancer Therapy". International Journal of Molecular Sciences. 24 (24): 17176. doi:10.3390/ijms242417176. ISSN 1422-0067. PMC 10743160. PMID 38139010.
  • Mosaddeghzadeh, Niloufar; Ahmadian, Mohammad Reza (2021-07-20). "The RHO Family GTPases: Mechanisms of Regulation and Signaling". Cells. 10 (7): 1831. doi:10.3390/cells10071831. ISSN 2073-4409. PMC 8305018. PMID 34359999.
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