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Draft:SMCO2

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  • Comment: None of the sources provided give significant coverage of the topic of this article. All are either database entries or passing mentions in papers about other subjects. For an article about a gene/protein we need significant coverage in reliable secondary sources that are specifically about the topic to a large extent (e.g. review articles). WeirdNAnnoyed (talk) 22:09, 19 December 2024 (UTC)
SMCO2
The red section depicts the N-terminus and the purple section depicts the C-terminus of the protein. The highlighted yellow region is illustrating the transmembrane region. This structure was predicted by AlphaFold and iCn3D was used to view/annotate the structure.
Tertiary Structure of SMCO2
The red section depicts the N-terminus and the purple section depicts the C-terminus of the protein. The highlighted yellow region is illustrating the transmembrane region.[1][2]
Identifiers
SymbolSMCO2
HGNC34448
RefSeqNM_001145010.3
UniProtA6NFE2
Other data
LocusChr. 12 p11.23
Search for
StructuresSwiss-model
DomainsInterPro

Single-pass membrane and coiled-coil domain-containing protein 2 is a protein that is encoded in humans by the SMCO2 gene. This gene is downregulated in brain tumors and potentially functions as a tumor suppressor.[3]

Gene

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Human SMCO2 is located on the plus strand at 12p11.23 and spans 78.9 kBp.[4] There are 9 predicted exons within this gene. SMCO2 lies between the genes BMAL2 and PPFIBP1.[5]

Transcripts

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There are 6 transcript variants of the SMCO2 gene.[4][5]

Transcript Variants of SMCO2
Transcript Variant mRNA Length

(nucleotides)

5’ UTR Length

(nucleotides)

3’ UTR Length

(nucleotides)

Protein Length

(amino acids)

Molecular Weight

(kDa)

1 1234 226 64 343 ~40
2 802 93 64 214 ~25
X1 1531 435 64 343 ~40
X2 3864 2951 64 282 ~32
X3 952 93 64 264 ~30
X4 686 100 46 179 ~21

Protein

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General Properties

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Human SMCO2 isoform 1 is 343 amino acids long with a molecular weight of ~40 kDa and an isoelectric point of 4.74.[6][7] It consists of 9 exons, 1 transmembrane region, and an upstream in-frame stop codon. There are 6 possible isoforms of the human SMCO2 protein.

Exons Present in Each Isoform of the SMCO2
Isoform Exon 1 Exon 2 Exon 3 Exon 4 Exon 5 Exon 6 Exon 7 Exon 8 Exon 9
1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
2 ✘ ✘ ✘ ✓ ✘ ✓ ✓ ✓ ✓
X1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
X2 ✘ ✘ ✘ ✓ ✓ ✓ ✓ ✓ ✓
X3 ✘ ✘ ✘ ✓ ✓ ✓ ✓ ✓ ✓
X4 ✘ ✓ ✓ ✓ ✓ * ✘ ✘ ✘

(*) With regards to SMCO2 isoform X4, only part of exon 6 is contained within the mRNA sequence. This is due to the polyadenylation sequence that is located 27 nucleotides upstream of the cleavage site.

Conceptual Translation of Human SMCO2[8]

Composition

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The SMCO2 protein has lower than normal amounts of glycine and proline. Glycine and proline are helix breakers. Due to the structural features of glycine and proline, the incorporation of these amino acids disrupts the stability of an alpha helix.[9] Proline has a structure that is too rigid to be incorporated into a helix. The structure of glycine is too flexible, therefore when it is incorporated into alpha helices, the helix shape transforms into a loop. The low amounts of these two amino acids in SMCO2 is important because the only secondary structure present in SMCO2 are alpha helices.

Domains

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SMCO2 has a single transmembrane region located near the C-terminus.[10] The N-terminus is located on the cytoplasmic side of the cell.

Expression

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Predicted secondary structure of the SMCO2 5’ UTR.
The yellow highlighted regions indicate conserved nucleotides in placental mammals. The binding sites for RNA binding proteins RBMX and MBNL1 are enlarged.[11]
Predicted secondary structure of the SMCO2 3’ UTR.
The yellow highlighted regions indicate conserved nucleotides in placental mammals and marsupials. The binding sites for RNA binding proteins RBMX, KHDRBS3, and SFRS13A are enlarged.[11]

Gene Level Regulation

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Human SMCO2 gene is ubiquitously expressed at low levels. The testis exhibits the highest level of mRNA expression.[12] Expression levels of SMCO2 has been shown to be lowered in lung epithelial cells of individuals with long term exposure to arsenic as well as in placental tissue of women with early and late onset preeclampsia.[13] In endometrial tissues, SMCO2 was found to be expressed in higher amounts in epithelial cells of individuals with polycystic ovary syndrome (PCOS).

Transcription Level Regulation

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The 5' and 3' untranslated region (UTR) of has a binding site for RNA Binding Motif Protein X-Linked (RBMX).[14] This gene, an active X chromosome homolog of the Y chromosome RBMY, is widely expressed.[15] On the other hand, the RBMY gene is only evolved in spermatogenesis. RBMX has been found to be involved in the suppression of the malignant progression of various tumors.[16]

Protein Level Regulation

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SMCO2 is predicted to be localized in the endoplasmic reticulum and the golgi apparatus of a cell.[17] SMCO2 has several post-translational modifications as well. A cleavage site exists near the N-terminus of the protein.[18] There are 2 conserved phosphorylation sites of SMCO2 in human and other placental mammals.[19] There is also a N-myristoylation site that is conserved in all placental mammals and marsupials.

Interacting Proteins

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CRISPR GI Screen has revealed that SMCO interacts with Signal Peptide Peptidase Like 3 (SPPL3).[20][21] SPPL3 enables aspartic endopeptidase activity, intramembrane cleaving and protein homodimerization activity.[22]

Evolution

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Corrected Sequence Divergence vs Date of Divergence. Graph shows the mutation rates of SMCO2 in comparison to the mutation rates of cytochrome C, fibrinogen A, and TMCO5A.

Paralogs

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SMCO2 has two known paralogs, TMCO5A and TMCO5B.

Orthologs of TMCO5A were found in placental mammals, marsupials, monotremes, and reptiles. TMCO5A is found in more evolutionarily distant species than SMCO2, suggesting that TMCO5A came first and SMCO2 split from it approximately 160-180 MYA (million years ago). TMCO5A is involved in spermiogenesis and associated with the manchette microtubules that play a role in sperm development.[23] This protein can be found in testis and endometrial tissues.[24]

TMCO5B is a pseudogene, therefore it is not able to code for a functional protein[25] TMCO5B first appeared in monotremes approximately 180-319 MYA.

Orthologs

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Unrooted phylogenetic tree displaying SMCO2 ancestry.[26]

Orthologs of SMCO2 are found in placental mammals and marsupials, but not in monotremes, birds, reptiles, amphibians, fish or invertebrates.[27] The tables below display some close orthologs (placental mammals) and distant orthologs (marsupials) of SMCO2.[5][6][28][29]

Selected Close Orthologs of SMCO2
Genus and Species Common Name Taxonomic Group Date of Divergence (MYA) Accession Number Protein Length (aa) Sequence Identity (%) Sequence Similarity (%)
Homo sapiens Human Primates 0 NP_001138482.1 343 100 100
Symphalangus syndactylus Siamang Primates 19.5 XP_055136271.2 342 92.4 95
Saimiri boliviensis Black-Capped Squirrel Monkey Primates 43 XP_003926650.2 343 78.7 88
Ochotona curzoniae Plateau Pika Lagomorpha 87 XP_040843351.1 358 44.7 63.6
Mus musculus House Mouse Rodentia 87 NP_081335.1 347 44.1 62.4
Meriones unguiculatus Mongolian Gerbil Rodentia 87 XP_021501667.1 357 39.2 58.1
Equus quagga Plains Zebra Perissodactyla 94 XP_046508708.1 345 63.4 78.4
Hippopotamus amphibius Hippopotamus Artiodactyla 94 XP_057556745.1 349 60.5 75.3
Molossus molossus Velvety Free-Tailed Bat Chiroptera 94 XP_036109125.1 359 55.6 70.1
Sus scrofa Wild Boar Artiodactyla 94 XP_020946895.1 369 54.8 69.4
Lontra canadensis North American River Otter Carnivora 94 XP_032711324.1 370 53.2 67.7
Hyaena hyaena Striped Hyena Carnivora 94 XP_039096760.1 370 53.1 69.4
Camelus ferus Wild Bactrian Camel Artiodactyla 94 XP_032328786.1 385 51.5 64.7
Selected Distant Orthologs of SMCO2
Genus and Species Common Name Taxonomic Group Date of Divergence (MYA) Accession Number Protein Length (aa) Sequence Identity (%) Sequence Similarity (%)
Phascolarctos cinereus Koala Diprotodontia 160 XP_020832803.1 347 32.7 51.2
Vombatus ursinus Common Wombat Diprotodontia 160 XP_027700116.1 373 30.9 50
Sarcophilus harrisii Tasmanian Devil Dasyuromorphia 160 XP_031793918.1 457 30 45.7
Monodelphis domestica Gray Short-Tailed Opossum Didelphimorphia 160 XP_056654368.1 479 28.2 43.7
Trichosurus vulpecula Common Brushtail Possom Diprotodontia 160 XP_036616684.1 386 25.4 35.5
Antechinus flavipes Yellow-Footed Antechinus Dasyuromorphia 160 XP_051817127.1 233 24.2 38.3
Dromiciops gliroides Colocolo Opossum Microbiotheria 160 XP_043823570.1 214 20.2 37

Clinical Significance

[edit]

Studies have determined that SMCO2 has associations with multiple conditions and diseases. SMCO2 was among the top ten downregulated genes in canine oligodendroglioma (ODG).[30] Patients with copy number variation (CNV) in a hotspot that encompasses SMCO2 and several other genes on chromosome 12 exhibit a range of phenotypes including developmental delay, abnormal facial shape, autism, intellectual disability, and seizures.[31] Mutations at various intron locations are associated with sleep apnea, hyperopia, and genetic susceptibility to lung cancer through the formation of lung carcinomas.[32][33][34][35]

References

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  1. ^ AlphaFold
  2. ^ iCn3D
  3. ^ Mitchell, D., Chintala, S., Fetcko, K., Henriquez, M., Tewari, B. N., Ahmed, A., Bentley, R. T., & Dey, M. (2019). Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets. Frontiers in oncology, 9, 780. https://doi.org/10.3389/fonc.2019.00780
  4. ^ a b Homo sapiens SMCO2 - NCBI mRNA
  5. ^ a b c Homo sapiens SMCO2 - NCBI Gene
  6. ^ a b Homo sapiens SMCO2 - NCBI Protein
  7. ^ Espasy
  8. ^ Bioline Six-Frame Translation Tool
  9. ^ Imai, K., & Mitaku, S. (2005). Mechanisms of secondary structure breakers in soluble proteins. Biophysics (Nagoya-shi, Japan), 1, 55–65. https://doi.org/10.2142/biophysics.1.55
  10. ^ SAPS Sequence Statistics
  11. ^ a b RNA Folding Form V2.3
  12. ^ SMCO2 - GeneCards
  13. ^ SMCO2 - NCBI GEO Profiles
  14. ^ SMCO2 5' and 3' UTR - RBPDB
  15. ^ Homo sapiens RBMX - NCBI Gene
  16. ^ Yan, Q., Zeng, P., Zhou, X., Zhao, X., Chen, R., Qiao, J., Feng, L., Zhu, Z., Zhang, G., & Chen, C. (2021). RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing. Oncogene, 40(15), 2635–2650. https://doi.org/10.1038/s41388-021-01666-z
  17. ^ DeepLoc
  18. ^ PSORTII
  19. ^ MotifScan
  20. ^ BioGrid
  21. ^ Yang, J., Guo, F., Chin, H. S., Chen, G. B., Ang, C. H., Lin, Q., Hong, W., & Fu, N. Y. (2023). Sequential genome-wide CRISPR-Cas9 screens identify genes regulating cell-surface expression of tetraspanins. Cell reports, 42(2), 112065. https://doi.org/10.1016/j.celrep.2023.112065
  22. ^ Homo sapiens SPPL3 - NCBI Gene
  23. ^ Kaneko, T., Minohara, T., Shima, S., Yoshida, K., Fukuda, A., Iwamori, N., Inai, T., & Iida, H. (2019). A membrane protein, TMCO5A, has a close relationship with manchette microtubules in rat spermatids during spermiogenesis. Molecular reproduction and development, 86(3), 330–341. https://doi.org/10.1002/mrd.23108
  24. ^ TMCO5A - Millipore Sigma
  25. ^ Homo sapiens TMCO5B - NCBI Gene
  26. ^ Phylogenetic Analysis
  27. ^ NCBI BLAST
  28. ^ EMBOSS Needle
  29. ^ TimeTree
  30. ^ Mitchell, D., Chintala, S., Fetcko, K., Henriquez, M., Tewari, B. N., Ahmed, A., Bentley, R. T., & Dey, M. (2019). Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets. Frontiers in oncology, 9, 780. https://doi.org/10.3389/fonc.2019.00780
  31. ^ Kul, D. A. M. (2019). Roles of the Hippo pathway kinase Ndr2 in neural development and behavior (Doctoral dissertation, Universitätsbibliothek Otto-von-Guericke-Universität). http://dx.doi.org/10.25673/25405
  32. ^ SMCO2 - GWAS
  33. ^ Cade, B. E., Chen, H., Stilp, A. M., Gleason, K. J., Sofer, T., Ancoli-Israel, S., Arens, R., Bell, G. I., Below, J. E., Bjonnes, A. C., Chun, S., Conomos, M. P., Evans, D. S., Johnson, W. C., Frazier-Wood, A. C., Lane, J. M., Larkin, E. K., Loredo, J. S., Post, W. S., Ramos, A. R., … Redline, S. (2016). Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans. American journal of respiratory and critical care medicine, 194(7), 886–897. https://doi.org/10.1164/rccm.201512-2431OC
  34. ^ Tideman, J. W. L., Pärssinen, O., Haarman, A. E. G., Khawaja, A. P., Wedenoja, J., Williams, K. M., Biino, G., Ding, X., Kähönen, M., Lehtimäki, T., Raitakari, O. T., Cheng, C. Y., Jonas, J. B., Young, T. L., Bailey-Wilson, J. E., Rahi, J., Williams, C., He, M., Mackey, D. A., Guggenheim, J. A., … UK Biobank Eye and Vision Consortium and the Consortium for Refractive Error and Myopia (CREAM Consortium) (2021). Evaluation of Shared Genetic Susceptibility to High and Low Myopia and Hyperopia. JAMA ophthalmology, 139(6), 601–609. https://doi.org/10.1001/jamaophthalmol.2021.0497
  35. ^ McKay, J. D., Hung, R. J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D. C., Caporaso, N. E., Johansson, M., Xiao, X., Li, Y., Byun, J., Dunning, A., Pooley, K. A., Qian, D. C., Ji, X., Liu, G., Timofeeva, M. N., Bojesen, S. E., Wu, X., Le Marchand, L., … Amos, C. I. (2017). Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nature genetics, 49(7), 1126–1132. https://doi.org/10.1038/ng.3892

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