KIAA2012

KIAA2012
Identifiers
Aliases	KIAA2012
External IDs	MGI: 2685819; HomoloGene: 124277; GeneCards: KIAA2012; OMA:KIAA2012 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q33.1 Start 202,073,255 bp [1] End 202,205,188 bp [1]
Gene location (Mouse) Chr. Chromosome 1 (mouse) [2] Band 1|1 C2 Start 59,555,423 bp [2] End 59,675,576 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube olfactory zone of nasal mucosa bronchial epithelial cell oocyte testicle gonad prefrontal cortex nucleus accumbens Brodmann area 9 pituitary gland Top expressed in spermatid testicle spermatocyte hypothalamus zygote urinary bladder primary oocyte secondary oocyte lip ovary More reference expression data BioGPS n/a
Orthologs Species Human Mouse 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 Mb Chr 1: 59.56 – 59.68 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/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

Ideogram of human chromosome 2 showing the location of KIAA2012.

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

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

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

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

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).

Structure

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.

Predicted KIAA2012 secondary structure with a 91.2% confidence level.

Post-translational modification

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

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

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

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

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

1. GRCh38: Ensembl release 89: ENSG00000182329 – Ensembl, May 2017
2. 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. 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. "KIAA2012 [Homo sapiens (human)]". NCBI. National Library of Medicine. Retrieved 1 Dec 2023.
7. "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. "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. Archived from the original on 15 December 2023. Retrieved 2 Dec 2023.
21. "KIAA2012 Results Summary". BioGRID. Retrieved 30 Nov 2023.
22. "STAG2 cohesion complex component". Gene -- NCBI. National Library of Medicine. Retrieved 3 Dec 2023.
23. "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.