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.[1]

Gene

KIAA2012 is located on the positive sense strand at position 2q33.1.[2] 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.[3] The RFX transcription factors, more specifically RFX1-6, bind to this highly conserved region and regulates cellular specialization and differentiation.[4] The image below shows the promoter region of KIAA2012 with the highly conserved RFX1-6 binding site.[3]

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.[1][5] KIAA2012 is expressed at lower levels in the liver, trachea, and testes.[6][7][8]

Protein

Unmodified KIAA2012 is 1,181 amino acids in length, has a molecular weight of 136 kdal, and an isoelectric pH around 8.[9][10]

Internal features

KIAA2012 is rich in glutamic acid and glutamine, and it is poor in valine.[9] There is also one mixed charge cluster between amino acids 951–1118.[11] There is one Domain of Unknown Function (DUF 4670) within KIAA2012 spanning from amino acid 635 to amino acid 1137.[2] Different than the whole KIAA2012, DUF 4670 is also rich in arginine and poor in glycine and phenylalanine.[9]

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.

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.[12] 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.[13][14]

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.[15] Shown in the table below, human KIAA2012 and two orthologs are listed with confidence values of where in the cell KIAA2012 is localized.[16]

KIAA2012 Localization with Confidence Percentages
NuclearPlasma MembraneCytoskeletalMitochondrialCytoplasmicSecretory Vesicles
Human82%4%9%4%------
Sardinian Tree Frog78%9%9%4%------
Zebrafish74%9%4%---9%4%

Function

KIAA2012 has predicted protein interactions with STAG2 and SMC1A.[17] STAG2 encodes a subunit of cohesion complexes used to regulate sister chromatid separation during cell division.[18] SMC1A is an important part of functional kinetochores due to its role in the multiprotein cohesion complex required for sister chromatid cohesion.[19] 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 NameAliasesLocation
SMC1ASMC1, SMCB, CDLS2, SB1.8, SMC1L1, DXS423E, SMC1alpha, RP6-29D12.1Xp11.22[19]
STAG2SA2, SA-2, SCC3B, bA517O1.1, RP11-517O1.1Xq25[18]

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 & SpeciesCommon NameDate of Divergenve (MYA)Accession #Sequence Length% Identity% Similarity
Homo sapiensHuman0NM_001277372.41181100100
Hylobates molochSilvery Gibbon19.5XP_032610815118194.296.4
Sciurus carolinensisGray Squirrel87XP_047398902113064.172.3
Mus caroliMouse87XP_029333762116061.372
Panthera unciaSnow Leopard94XP_049471125118075.382.7
Orcinus orcaKiller Whale94XP_033285753117274.582.7
Bubalus bubalisWater Buffalo94XP_006080602118572.981.1
Alligator mississippiensisAmerican Alligator319XP_059583055132537.149.7
Caretta carettaLoggerhead Turtle319XP_04872505413293751.4
Chelonia mydasGreen Sea Turtle319XP_037768210132536.850.9
Crotalus tigrisTiger Rattlesnake319XP_039210533122032.446.9
Xenopus tropicalisWestern Clawed Frog352XP_031749269133931.945.8
Rhinatrema bivittatumTwo-Lined Caecilian352XP_029462137149930.644.8
Spea bombifronsPlains Spadefoot Toad352XP_053326593143629.644
Hyla sardaSardinian Tree Frog352XP_056391303142829.544.9
Protopterus annectensWest African Lungfish408XP_043931036141229.845
Takifugu rubripesJapanese Puffer429XP_029701411112925.339.4
Danio rerioZebrafish429XP_009302807148424.937.1
Anarrhichthys ocellatusWolf Eel429XP_031729884120423.937.3
Amblyraja radiataThorny Skate462XP_032880336139225.740.5

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.[20] Additionally, KIAA2012 is down regulated in women with polycystic ovary syndrome (PCOS) compared to women without PCOS.[21]

References

  1. ^ Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M (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
  2. ^ "KIAA2012 [Homo sapiens (human)]". NCBI. National Library of Medicine. Retrieved 1 Dec 2023.
  3. ^ "USCS Genomics Institute". Genome Browser. Retrieved 30 Nov 2023.
  4. ^ Sugiaman-Trapman D, Vitezic M, Jouhilahti EM, Mathelier A, Lauter G, Misra S, Daub CO, Kere J, Swoboda P (March 2018). "Characterization of the human RFX transcription factor family by regulatory and target gene analysis". BMC Genomics. 19 (1). doi:10.1186/s12864-018-4564-6. PMC 5838959. PMID 29510665
  5. ^ "Illumina bodyMap2 Transcriptome". NCBI. BioProject. Retrieved 10 Dec 2023.
  6. ^ Szabo L, Morey R, Palpant NJ, Wang PL, Afari N, Jiang C, Parast MM, Murry CE, Laurent LC, Salzman J (June 2015). "Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development". Genome Biology. 16 (1). doi:10.1186/s13059-015-0690-5. PMC 4506483. PMID 26076956
  7. ^ Duff MO, Olson S, Wei X, Garrett SC, Osman A, Bolisetty M, Plocik A, Celniker SE, Graveley BR (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
  8. ^ "Tissue Expression Type -- KIAA2012". The Human Protein Atlas. Retrieved 8 Nov 2023.
  9. ^ "SAPS Results". European Bioinformatic Institute. Retrieved 29 Nov 2023.
  10. ^ Tokmakov AA, Kurotani A, Sato KI (2021). "Protein pI and Intracellular Localization". Frontiers in Molecular Biosciences. 8. doi:10.3389/fmolb.2021.775736. PMC 8667598. PMID 34912847
  11. ^ 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
  12. ^ 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
  13. ^ 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
  14. ^ Nestler, Eric J & Greengard, Paul (1999). "Protein Phosphorylation is of Fundamental Importance in Biological Regulation". Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6. Retrieved 10 Dec 2023.
  15. ^ 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
  16. ^ "YLoc". Iterpretable Subcellular Localization Prediction. Archived from the original on 15 December 2023. Retrieved 2 Dec 2023.
  17. ^ "KIAA2012 Results Summary". BioGRID. Retrieved 30 Nov 2023.
  18. ^ "STAG2 cohesion complex component". Gene -- NCBI. National Library of Medicine. Retrieved 3 Dec 2023.
  19. ^ "SMC1A - structural maintenance of chromosome 1A (human)". PubChem. National Library of Medicine. Retrieved 3 Dec 2023.
  20. ^ "The NHGRI-EBI Catalog of human genome-wide association studies". GWAS Catalog. Retrieved 10 Dec 2023.
  21. ^ Hiam D, Simar D, Laker R, Altıntaş A, Gibson-Helm M, Fletcher E, Moreno-Asso A, Trewin AJ, Barres R, Stepto NK (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