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KIAA2012
Identifiers
AliasesKIAA2012
External IDsMGI: 2685819; HomoloGene: 124277; GeneCards: KIAA2012; OMA:KIAA2012 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

100652824

381260

Ensembl

ENSG00000182329

ENSMUSG00000047361

UniProt

Q0VF49

n/a

RefSeq (mRNA)

NM_001080445
NM_001277372
NM_001367720

NM_001013771
NM_001357842

RefSeq (protein)

NP_001264301
NP_001354649

n/a

Location (UCSC)Chr 2: 202.07 – 202.21 MbChr 1: 59.56 – 59.68 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

KIAA2012 is a protein which, in humans, is encoded by the KIAA2012 gene. KIAA2012 is expressed at very low levels throughout the body, but it is primarily expressed in the ovary, lungs, and brain.[5]

Gene

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Ideogram of human chromosome 2 showing the location of KIAA2012 (Image generated using BioRender).

KIAA2012 is located on the positive sense strand at position 2q33.1.[6] KIAA2012 has 24 exons, and it spans 131,934 bases including introns. No aliases or common names are used in addition to KIAA2012.

Gene level regulation

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Within the promoter region of KIAA2012, there is a highly conserved transcription factor binding site that has no common SNPs.[7] The RFX transcription factors, more specifically RFX1-6, bind to this highly conserved region and regulates cellular specialization and differentiation.[8] The image below shows the promoter region of KIAA2012 with the highly conserved RFX1-6 binding site.[7]

Human KIAA2012 promoter sequence. In red are common SNPs, highlighted in yellow is the conserved RFX1-6 transcription factor binding site, and the bolded letters show the transcription start site.

mRNA

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KIAA2012 is expressed differentially in the body at low levels. Of this overall low expression, KIAA2012 is expressed most highly in the brain, lungs, and ovary.[5][9] KIAA2012 is expressed at lower levels in the liver, trachea, and testes.[10][11][12]

Protein

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Unmodified KIAA2012 is 1,181 amino acids in length, has a molecular weight of 136 kdal, and an isoelectric pH around 8.[13][14]

Internal features

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KIAA2012 is rich in glutamic acid and glutamine, and it is poor in valine.[13] There is also one mixed charge cluster between amino acids 951–1118.[15] There is one Domain of Unknown Function (DUF 4670) within KIAA2012 spanning from amino acid 635 to amino acid 1137.[6] Different than the whole KIAA2012, DUF 4670 is also rich in arginine and poor in glycine and phenylalanine.[13]

Schematic of KIAA2012 with annotations showing the Glutamine (E) and Glutamic Acid (Q) rich regions, DUF 4670, and the mixed charge cluster (MCC). (Made using IBS Online Drawing Tool).

Structure

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The secondary structure of KIAA2012 consists primarily of alpha helices. On the left, a high confidence prediction of the secondary structure is shown. On the right, the entire 3-D structure is shown, showing how the alpha helices fold to form the entire KIAA2012 protein.

Predicted folding pattern and 3-D structure of KIAA2012. (Image generated by I-Tasser Online Tool).
Predicted KIAA2012 secondary structure with a 91.2% confidence level. (Image generated by Phyre 2.0)

Post-translational modification

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KIAA2012 has a highly conserved cGMP-dependent protein kinase binding domain. These cGMP-dependent protein kinases (PRKG) are a part of the NO/cGMP signaling pathway, and they are important factors in many signal transduction processes.[16] Additionally, there are many potential sites for phosphorylation, SUMOylation, and myristoylation. In instances where KIAA2012 is post-translationally modified in these ways, the resulting charge, structure, function, and sub-cellular localization can be altered.[17][18]

Sub-cellular Localization

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Proteins tagged with localization signals will be transported to various regions of the cell. KIAA2012 contains nuclear localization signal sequences, which are short stretches of amino acids that moderate transportation of nuclear proteins to the nucleus.[19] Shown in the table below, human KIAA2012 and two orthologs are listed with confidence values of where in the cell KIAA2012 is localized.[20]

KIAA2012 Localization with Confidence Percentages
Nuclear Plasma Membrane Cytoskeletal Mitochondrial Cytoplasmic Secretory Vesicles
Human 82% 4% 9% 4% --- ---
Sardinian Tree Frog 78% 9% 9% 4% --- ---
Zebrafish 74% 9% 4% --- 9% 4%

Function

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KIAA2012 has predicted protein interactions with STAG2 and SMC1A.[21] STAG2 encodes a subunit of cohesion complexes used to regulate sister chromatid separation during cell division.[22] SMC1A is an important part of functional kinetochores due to its role in the multiprotein cohesion complex required for sister chromatid cohesion.[23] Because KIAA2012 is localized in the nucleus and interacts with STAG2 and SMC1A, its role as a protein surrounds DNA manipulation or cell division.

Predicted Proteins that Interact with KIAA2012
Protein Name Aliases Location
SMC1A SMC1, SMCB, CDLS2, SB1.8, SMC1L1, DXS423E, SMC1alpha, RP6-29D12.1 Xp11.22[23]
STAG2 SA2, SA-2, SCC3B, bA517O1.1, RP11-517O1.1 Xq25[22]

Homology and evolution

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Twenty organisms with a KIAA2012 ortholog are shown below, and they are sorted by date of divergence and sequence identity. There were no orthologs found in birds, but ortholog versions of KIAA2012 exist in mammals, reptiles, amphibians, and fish. An unrooted phylogenetic tree showing each taxonomic group and their divergence patterns can be found below the ortholog table.

Genus & Species Common Name Date of Divergenve (MYA) Accession # Sequence Length % Identity % Similarity
Homo sapiens Human 0 NM_001277372.4 1181 100 100
Hylobates moloch Silvery Gibbon 19.5 XP_032610815 1181 94.2 96.4
Sciurus carolinensis Gray Squirrel 87 XP_047398902 1130 64.1 72.3
Mus caroli Mouse 87 XP_029333762 1160 61.3 72
Panthera uncia Snow Leopard 94 XP_049471125 1180 75.3 82.7
Orcinus orca Killer Whale 94 XP_033285753 1172 74.5 82.7
Bubalus bubalis Water Buffalo 94 XP_006080602 1185 72.9 81.1
Alligator mississippiensis American Alligator 319 XP_059583055 1325 37.1 49.7
Caretta caretta Loggerhead Turtle 319 XP_048725054 1329 37 51.4
Chelonia mydas Green Sea Turtle 319 XP_037768210 1325 36.8 50.9
Crotalus tigris Tiger Rattlesnake 319 XP_039210533 1220 32.4 46.9
Xenopus tropicalis Western Clawed Frog 352 XP_031749269 1339 31.9 45.8
Rhinatrema bivittatum Two-Lined Caecilian 352 XP_029462137 1499 30.6 44.8
Spea bombifrons Plains Spadefoot Toad 352 XP_053326593 1436 29.6 44
Hyla sarda Sardinian Tree Frog 352 XP_056391303 1428 29.5 44.9
Protopterus annectens West African Lungfish 408 XP_043931036 1412 29.8 45
Takifugu rubripes Japanese Puffer 429 XP_029701411 1129 25.3 39.4
Danio rerio Zebrafish 429 XP_009302807 1484 24.9 37.1
Anarrhichthys ocellatus Wolf Eel 429 XP_031729884 1204 23.9 37.3
Amblyraja radiata Thorny Skate 462 XP_032880336 1392 25.7 40.5
Unrooted phylogenetic tree of the KIAA2012 orthologs found in Table 1.  Mammals (yellow), reptiles (red), amphibians (green), and fish (blue) are circled to differentiate between them, and images of each species are provided next to the three-letter code

Clinical significance

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There are several genome-wide association studies that report traits associated variations in KIAA2012. The reported traits with the highest number of associations are heel bone mineral density, taste liking measurement, educational attainment, lung function, and height.[24] Additionally, KIAA2012 is down regulated in women with polycystic ovary syndrome (PCOS) compared to women without PCOS.[25]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000182329 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047361 – 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 Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. (February 2014). "Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics". Molecular & Cellular Proteomics. 13 (2): 397–406. doi:10.1074/mcp.M113.035600. PMC 3916642. PMID 24309898.
  6. ^ a b "KIAA2012 [Homo sapiens (human)]". NCBI. National Library of Medicine. Retrieved 1 Dec 2023.
  7. ^ a b "USCS Genomics Institute". Genome Browser. Retrieved 30 Nov 2023.
  8. ^ Sugiaman-Trapman D, Vitezic M, Jouhilahti EM, Mathelier A, Lauter G, Misra S, et al. (March 2018). "Characterization of the human RFX transcription factor family by regulatory and target gene analysis". BMC Genomics. 19 (1): 181. doi:10.1186/s12864-018-4564-6. PMC 5838959. PMID 29510665.
  9. ^ "Illumina bodyMap2 Transcriptome". NCBI. BioProject. Retrieved 10 Dec 2023.
  10. ^ Szabo L, Morey R, Palpant NJ, Wang PL, Afari N, Jiang C, et al. (June 2015). "Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development". Genome Biology. 16 (1): 126. doi:10.1186/s13059-015-0690-5. PMC 4506483. PMID 26076956.
  11. ^ Duff MO, Olson S, Wei X, Garrett SC, Osman A, Bolisetty M, et al. (May 2015). "Genome-wide identification of zero nucleotide recursive splicing in Drosophila". Nature. 521 (7552): 376–379. Bibcode:2015Natur.521..376D. doi:10.1038/nature14475. PMC 4529404. PMID 25970244.
  12. ^ "Tissue Expression Type -- KIAA2012". The Human Protein Atlas. Retrieved 8 Nov 2023.
  13. ^ a b c "SAPS Results". European Bioinformatic Institute. Retrieved 29 Nov 2023.
  14. ^ Tokmakov AA, Kurotani A, Sato KI (2021). "Protein pI and Intracellular Localization". Frontiers in Molecular Biosciences. 8: 775736. doi:10.3389/fmolb.2021.775736. PMC 8667598. PMID 34912847.
  15. ^ Zhu ZY, Karlin S (August 1996). "Clusters of charged residues in protein three-dimensional structures". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8350–8355. Bibcode:1996PNAS...93.8350Z. doi:10.1073/pnas.93.16.8350. PMC 38674. PMID 8710874.
  16. ^ Wolfertstetter S, Huettner JP, Schlossmann J (February 2013). "cGMP-Dependent Protein Kinase Inhibitors in Health and Disease". Pharmaceuticals. 6 (2): 269–286. doi:10.3390/ph6020269. PMC 3816681. PMID 24275951.
  17. ^ Maejima Y, Sadoshima J (September 2014). "SUMOylation: a novel protein quality control modifier in the heart". Circulation Research. 115 (8): 686–689. doi:10.1161/CIRCRESAHA.114.304989. PMC 4181369. PMID 25258400.
  18. ^ Nestler EJ, Greengard P (1999). "Protein Phosphorylation is of Fundamental Importance in Biological Regulation". Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6. Retrieved 10 Dec 2023.
  19. ^ Cokol M, Nair R, Rost B (November 2000). "Finding nuclear localization signals". EMBO Reports. 1 (5): 411–415. doi:10.1093/embo-reports/kvd092. PMC 1083765. PMID 11258480.
  20. ^ "YLoc". Iterpretable Subcellular Localization Prediction. Retrieved 2 Dec 2023.
  21. ^ "KIAA2012 Results Summary". BioGRID. Retrieved 30 Nov 2023.
  22. ^ a b "STAG2 cohesion complex component". Gene -- NCBI. National Library of Medicine. Retrieved 3 Dec 2023.
  23. ^ a b "SMC1A - structural maintenance of chromosome 1A (human)". PubChem. National Library of Medicine. Retrieved 3 Dec 2023.
  24. ^ "The NHGRI-EBI Catalog of human genome-wide association studies". GWAS Catalog. Retrieved 10 Dec 2023.
  25. ^ Hiam D, Simar D, Laker R, Altıntaş A, Gibson-Helm M, Fletcher E, et al. (December 2019). "Epigenetic Reprogramming of Immune Cells in Women With PCOS Impact Genes Controlling Reproductive Function". The Journal of Clinical Endocrinology and Metabolism. 104 (12): 6155–6170. doi:10.1210/jc.2019-01015. hdl:10536/DRO/DU:30130006. PMID 31390009.
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