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KIAA2013

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KIAA2013, also known as Q8IYS2[1] or MGC33867[2], is a single-pass transmembrane protein encoded by the KIAA2013 gene in humans.[1] The complete function of KIAA2013 has not yet been fully elucidated.

Gene

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The KIAA2013 gene is located on the short arm of Chromosome 1, in location 36.22 (1p36.22).[3] It can be found on the minus strand of the previously mentioned chromosome, running from 11,986,485 to 11,979,643.[4] The gene contains 3 exons, 2 introns, and is 6,838 base pairs long.[3]

mRNA

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Splice Variants

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There are two alternate splice variants. One retains a transcript length of 2539 bp and the other retains a transcript length of 2170.[5]

Protein

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Physical Characteristics

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The longest mRNA splice variant of the KIAA2013 protein contains 634 amino acid residues. The predicted weight of the protein is 69.2 kDa[6] and its isoelectric point is 8.44. There is also a Lysine multiplet of six amino acid residues in a row, beginning in position 28.[7] This sequence, however, is located within the cleavable signal peptide and will most likely not remain a part of the mature protein.

Conserved Domains

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KIAA2013 contains one conserved protein domain of unknown function by the name of DUF2152, or pfam10222. This protein has remained conserved from mammals to invertebrates.[8] The conserved domain extends from amino acid position 6 to 629.

Secondary Structure

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Secondary structure as analyzed via GOR4[9]:

Structure Percentage
Alpha helix 38%
Beta sheet 61.2%

Tertiary Structure

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iCn3D illustration of the three disulfide bridges formed within the KIAA2013 protein tertiary structure.

An AlphaFold prediction has been generated that was further analyzed through the use of iCn3D.[10] The following images highlight the transmembrane regions of the KIAA2013 protein, as well as the three disulfide bridges that can be seen to form.

iCn3D illustration of the transmembrane region of the KIAA2013 protein. This region is entirely a helical structure.

Gene Level Regulation

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Promoter

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The singular human KIAA2013 promoter is a 1194 bp long sequence that precedes the gene.[11]

Transcription Factor Binding Sites

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There are hundreds of possible transcription factor binding sites that can be found on the promoter sequence of KIAA2013. Here is a list of some that retain a high matrix similarity:

Tissue Expression

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NCBI GEO KIAA2013 expression data as it stands regarding normal tissue samples in the human body.

The KIAA2013 protein has been shown to be expressed ubiquitously across many differing human tissues. However, studies suggest that the small intestine, most specifically the duodenum, as well as the colon and kidneys express higher levels of this protein.[12] RNA-seq data has indicated that this gene is also expressed within the intestine of 20 week old fetuses.[3] NCBI GEO data of preimplantation embryos indicates that KIAA2013 expression begins to be expressed in high amounts after the 4-cell embryo has developed.[13]

Transcript Level Regulation

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3' UTR

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As can be seen in the image, this final portion of the KIAA2013 3' UTR contains the poly-a signal as well as multiple ELAVL1 miRNA binding sites. ELAVL1 is a necessary RNA binding protein during the process of placental branching and general embryonic development. Out of the womb, ELAVL1 promotes angiogenesis, or the formation of new blood vessels.[14]

This image captures the end of the 3' UTR, wherein several ELAVL1 miRNA binding sites and one poly-a site can be seen.
5' UTR illustrating the miRNA binding sites of EIF4b, FUS, RBM4, as well as a couple of stop-codons.

5' UTR

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The 5’ UTR has two main conserved regions, located at the very beginning and very end of the sequence. Not only that, but it has two sequences coding for stop codons, as can be seen in the image. Most miRNA seem to congregate around the two conserved domains. EIF4B is known as eukaryotic translation initiation factor 4B and is needed to bind mRNAs to ribosomes as well as assist with the translation of longer 5' UTRs.[15] It binds to the mRNA in the presence of ATP. FUS actually mediates gene silencing.[16] It has also been clinically linked with ALS diagnosis cases.[16] Finally, RBM4 helps to control translation as well as alternative splicing events. Reduced expression of this miRNA has been linked to Down Syndrome.[17]

Protein Level Regulation

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Subcellular Localization

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KIAA2013 has been found to intracellularly localize to the Golgi apparatus and endoplasmic reticulum. This has been validated through the use of GFP fusion and antibody specific experimentation.[18] DeepLoc analysis has indicated that there is an 81.94% chance that this protein is found in the Golgi apparatus and 16.77% that it is localized to the endoplasmic reticulum.[19] The likelihood that KIAA2013 is a membrane protein sits at 99.98%. [19]

Post-Translational Modifications

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There is a predicted signal peptide spanning across amino acids 1-40.[20] The cleavage site for this signal peptide is located between amino acid positions 40 and 41. There are also a collection of post-translational modifications that can be connected with KIAA2013. They include:

KIAA2013 Post-Translational Modifications
Modification Location
Glycosylation T224[21]
Glycosylation N363[21]
Phosphorylation S159[22]
Phosphorylation S381[22]
Ubiquitylation K629[23]

Homology and Protein Divergence

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Paralogs

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There are currently no known paralogs of KIAA2013.

Pseudogene

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KIAA2013 has one pseudogene found within Homo sapiens named LOC728138. The length of this pseudogene is 633 amino acid residues and it shares a 96.8% sequence identity with KIAA2013.[24]

Orthologs

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There are orthologs for KIAA2013 ranging from mammals all the way back to invertebrates. As of now, there are 419 organisms that are known to contain orthologs of this gene.[25]

Table of KIAA2013 Orthologs
KIAA2013 Genus, species Common Name Divergence Date (MYA) Accession Number Protein Length Seq. Identity Seq. Similarity
Mammalia Homo sapiens Human 0 NP_612355.1 634 100% 100%
Mus caroli Ryuku mouse 90 XP_021016690.1 634 91.8% 95.9%
Mirounga leonina Southern elephant seal 94 XP_034875674.1 629 94.8% 96.8%
Felis catus Cat 96 XP_003989629.3 634 94.8% 97.1%
Aves Falco rusticolus Gyrfalcon 312 XP_037236550.1 612 61.7% 71%
Reptilia Gopherus evgoodei Goode's thornscrub tortoise 312 XP_030393408.1 623 64.9% 74.9%
Amphibian Xenopus laevis African clawed frog 352 XP_018083185.1 614 55.5% 69.1%
Microcaecelia unicolor Tiny Cayenne Caecilian 352 XP_030078049.1 623 53% 68.4%
Fish Acipenser ruthenus Sterlet 435 XP_033899255.2 610 56.5% 69.3%
Lepisosteus oculatus Spotted gar 435 XP_006642029.2 623 55.1% 68.1%
Invertebrates Anopheles merus Mosquito 797 XP_041777166.1 625 27.5% 44.5%
Pollicipes pollicipes Goose Neck Barnacle 797 XP_037086897.1 639 27.6% 44.3%
Drosophila subpulchrella Fly 797 XP_037708712.1 637 26% 43%
Limulus polyphemus Atlantic Horseshoe crab 797 XP_013773544.2 516 21.8% 36.8%

Protein Evolution

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The graph to the right illustrates the rate of divergence of the protein KIAA2013, as compared to cytochrome c and fibrinogen alpha. This graph utilized a molecular clock approach wherein the evolution of the protein KIAA2013 was compared to the rate of the two previously mentioned proteins. Cytochrome c has a much slower rate of divergence as compared to fibrinogen alpha, while KIAA2013 lies in between the two.[26]

The evolution of KIAA2013, as compared to fibrinogen alpha and cytochrome c.

Interacting Proteins

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KIAA2013 has been found to interact with two proteins: TMEM60 and IBP5 via a validated two-hybrid array. [27]

Clinical Significance

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KIAA2013 has been found to play a role in the Endocannabinoid system. This system is made up of cannabinoid receptors 1 and 2 (CB1 and CB2) as well as the various ligands and enzymes that interact. The protein KIAA2013 has been found to be expressed within CB2 expressing cells.[28]Both cannabinoid receptors are labeled as class A G-Protein Coupled Receptors, and CB2 is highly expressed within the human spleen and leukocytes. CB2, and by extension KIAA2013, are therefore targets of interest for therapeutic studies looking into diseases such as inflammatory bowel disease and rheumatoid arthritis.[29]


  1. ^ a b "KIAA2013 - Uncharacterized protein KIAA2013 precursor - Homo sapiens (Human) - KIAA2013 gene & protein". www.uniprot.org. Retrieved 2021-12-17.
  2. ^ "KIAA2013".{{cite web}}: CS1 maint: url-status (link)
  3. ^ a b c "KIAA2013 KIAA2013 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-17.
  4. ^ "AceView: Gene:KIAA2013, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2021-12-17.
  5. ^ "Gene: KIAA2013 (ENSG00000116685) - Splice variants - Homo_sapiens - Ensembl genome browser 105". useast.ensembl.org. Retrieved 2021-12-18.
  6. ^ "KIAA2013 Antibody (27886-1-AP)". www.thermofisher.com. Retrieved 2021-12-18.
  7. ^ "PSORT II Prediction". psort.hgc.jp. Retrieved 2021-12-18.
  8. ^ "CDD Conserved Protein Domain Family: DUF2152". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
  9. ^ "NPS@ : GOR4 secondary structure prediction". npsa-prabi.ibcp.fr. Retrieved 2021-12-18.
  10. ^ "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2021-12-18.
  11. ^ "GXP_42188(KIAA2013/human)".{{cite web}}: CS1 maint: url-status (link)
  12. ^ "GDS3113 / 706030". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
  13. ^ "GDS3959 / 224706_at". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
  14. ^ Chang, Sung-Hee; Elemento, Olivier; Zhang, Jiasheng; Zhuang, Zhen W.; Simons, Michael; Hla, Timothy (2014-12-23). "ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis". Proceedings of the National Academy of Sciences of the United States of America. 111 (51): 18309–18314. doi:10.1073/pnas.1412172111. ISSN 0027-8424. PMC 4280608. PMID 25422430.
  15. ^ Sen, Neelam Dabas; Zhou, Fujun; Harris, Michael S.; Ingolia, Nicholas T.; Hinnebusch, Alan G. (2016-09-20). "eIF4B stimulates translation of long mRNAs with structured 5′ UTRs and low closed-loop potential but weak dependence on eIF4G". Proceedings of the National Academy of Sciences. 113 (38): 10464–10472. doi:10.1073/pnas.1612398113. ISSN 0027-8424. PMID 27601676.
  16. ^ a b Zhang, Tao; Wu, Yen-Ching; Mullane, Patrick; Ji, Yon Ju; Liu, Honghe; He, Lu; Arora, Amit; Hwang, Ho-Yon; Alessi, Amelia F.; Niaki, Amirhossein G.; Periz, Goran (2018-03-01). "FUS Regulates Activity of MicroRNA-mediated Gene Silencing". Molecular cell. 69 (5): 787–801.e8. doi:10.1016/j.molcel.2018.02.001. ISSN 1097-2765. PMC 5836505. PMID 29499134.
  17. ^ D, Dhananjaya; Hung, Kuan-Yang; Tarn, Woan-Yuh (2018-06-15). "RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development". Molecular and Cellular Biology. 38 (12). doi:10.1128/MCB.00007-18. ISSN 0270-7306. PMC 5974434. PMID 29581187.{{cite journal}}: CS1 maint: PMC format (link)
  18. ^ Kandasamy, Kumaran; Keerthikumar, Shivakumar; Goel, Renu; Mathivanan, Suresh; Patankar, Nandini; Shafreen, Beema; Renuse, Santosh; Pawar, Harsh; Ramachandra, Y. L.; Acharya, Pradip Kumar; Ranganathan, Prathibha (2009-01-01). "Human Proteinpedia: a unified discovery resource for proteomics research". Nucleic Acids Research. 37 (suppl_1): D773–D781. doi:10.1093/nar/gkn701. ISSN 0305-1048.
  19. ^ a b "Summary of 1 predicted sequences".{{cite web}}: CS1 maint: url-status (link)
  20. ^ "RecName: Full=Uncharacterized protein KIAA2013; Flags: Precursor - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
  21. ^ a b "KIAA2013 - Uncharacterized protein KIAA2013 precursor - Homo sapiens (Human) - KIAA2013 gene & protein". www.uniprot.org. Retrieved 2021-12-18.
  22. ^ a b "KIAA2013 (human)". www.phosphosite.org. Retrieved 2021-12-18.
  23. ^ "KIAA2013 (RP5-1077B9.1) Result Summary | BioGRID". thebiogrid.org. Retrieved 2021-12-18.
  24. ^ "LOC728138 protein [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
  25. ^ "ortholog_gene_90231[group] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-18.
  26. ^ Ho, Simon Y. W.; Duchêne, Sebastián (2014). "Molecular-clock methods for estimating evolutionary rates and timescales". Molecular Ecology. 23 (24): 5947–5965. doi:10.1111/mec.12953. ISSN 1365-294X.
  27. ^ Luck, Katja; Kim, Dae-Kyum; Lambourne, Luke; Spirohn, Kerstin; Begg, Bridget E.; Bian, Wenting; Brignall, Ruth; Cafarelli, Tiziana; Campos-Laborie, Francisco J.; Charloteaux, Benoit; Choi, Dongsic (2020-04). "A reference map of the human binary protein interactome". Nature. 580 (7803): 402–408. doi:10.1038/s41586-020-2188-x. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
  28. ^ Sharaf, Ahmed; Mensching, Leonore; Keller, Christina; Rading, Sebastian; Scheffold, Marina; Palkowitsch, Lysann; Djogo, Nevena; Rezgaoui, Meriem; Kestler, Hans A.; Moepps, Barbara; Failla, Antonio Virgilio (2019). "Systematic Affinity Purification Coupled to Mass Spectrometry Identified p62 as Part of the Cannabinoid Receptor CB2 Interactome". Frontiers in Molecular Neuroscience. 12: 224. doi:10.3389/fnmol.2019.00224. ISSN 1662-5099.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  29. ^ Oyagawa, Caitlin R. M.; Grimsey, Natasha L. (2021-01-01), Shukla, Arun K. (ed.), "Chapter 5 - Cannabinoid receptor CB1 and CB2 interacting proteins: Techniques, progress and perspectives", Methods in Cell Biology, Biomolecular Interactions Part A, vol. 166, Academic Press, pp. 83–132, retrieved 2021-12-18
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