Biology:HNRNPK

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Heterogeneous nuclear ribonucleoprotein K (also protein K) is a protein that in humans is encoded by the HNRNPK gene.[1] It is found in the cell nucleus that binds to pre-messenger RNA (mRNA) as a component of heterogeneous ribonucleoprotein particles. The simian homolog is known as protein H16. Both proteins bind to single-stranded DNA as well as to RNA and can stimulate the activity of RNA polymerase II, the protein responsible for most gene transcription. The relative affinities of the proteins for DNA and RNA vary with solution conditions and are inversely correlated, so that conditions promoting strong DNA binding result in weak RNA binding.[2]

RNA binding protein domains in other proteins that are similar to the RNA binding domain of protein K are called K-homology or KH domains.

Protein K has been the subject of study related to colorectal cancer, in which an RNA editing event inducing the expression of an isoform containing a point mutation was found to be specific to cancerous cells.[3]

Function

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA-binding proteins, and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm.

The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene is located in the nucleoplasm and has three repeats of KH domains that binds to RNAs. It is distinct among other hnRNP proteins in its binding preference; it binds tenaciously to poly(C). This protein is also thought to have a role during cell cycle progression. Multiple alternatively spliced transcript variants have been described for this gene, but only three variants have been fully described.[4]

Mutations in both copies of HNRNPK are embryonic lethal in mice. Mice with both copies of the gene knocked out die before the 14th day of embryonic development.[5]

Clinical significance

Okamoto syndrome

Mutations in HNRNPK cause Okamoto syndrome, also known as Au–Kline syndrome.[6]

Blood cancers

Deletions in the region encompassing HNRNPK have been found in the cells of acute myeloid leukemia in approximately 2% of cases. Additionally, a majority of mice who have had one of their HNRNPK genes artificially knocked out developed myeloid cancers, with a third developing lymphoid cancers and 4% developing hepatocellular carcinomas. The mice were also smaller, had less developed organs and had higher postnatal mortality (30%). The median lifespan of the mice that survived was less than 50% that of wild-type mice. Deficiencies in HNRNPK appear to specifically reduce the levels of the p42 isoform of CEBPA, which is a transcription factor involved in the differentiation of certain blood cells, as well as p21 (cyclin-dependent kinase inhibitor 1), which is involved in pausing cell development for DNA repair.[7]

HNRNPK overexpression also appears to contribute to cancers via a different mechanism involving translation rather than transcription.[7]

Interactions

HNRPK has been shown to interact with:

Human proteins containing a KH domain

AKAP1; ANKHD1; ANKRD17; ASCC1; BICC1; DDX43; DDX53; DPPA5; FMR1; FUBP1; FUBP3; FXR1; FXR2; HDLBP; HNRPK; IGF2BP1; IGF2BP2; IGF2BP3; KHDRBS1; KHDRBS2; KHDRBS3; KHSRP; KRR1; MEX3A; MEX3B; MEX3C; MEX3D; NOVA1; NOVA2; PCBP1; PCBP2; PCBP3; PCBP4; PNO1; PNPT1; QKI; SF1; TDRKH;

References

  1. ↑ "Identification, molecular cloning, expression and chromosome mapping of a family of transformation upregulated hnRNP-K proteins derived by alternative splicing". Journal of Molecular Biology 236 (1): 33–48. February 1994. doi:10.1006/jmbi.1994.1116. PMID 8107114. 
  2. ↑ "Identity of the RNA-binding protein K of hnRNP particles with protein H16, a sequence-specific single strand DNA-binding protein". Nucleic Acids Research 22 (20): 4183–6. October 1994. doi:10.1093/nar/22.20.4183. PMID 7524036. 
  3. ↑ "Editing of hnRNP K protein mRNA in colorectal adenocarcinoma and surrounding mucosa". British Journal of Cancer 94 (4): 586–92. February 2006. doi:10.1038/sj.bjc.6602938. PMID 16404425. 
  4. ↑ "Entrez Gene: HNRPK heterogeneous nuclear ribonucleoprotein K". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3190. 
  5. ↑ "hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies". Cancer Cell 28 (4): 486–499. October 2015. doi:10.1016/j.ccell.2015.09.001. PMID 26412324. 
  6. ↑ Reference, Genetics Home. "Au-Kline syndrome" (in en). https://ghr.nlm.nih.gov/condition/au-kline-syndrome. 
  7. ↑ 7.0 7.1 "hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies". Cancer Cell 28 (4): 486–499. October 2015. doi:10.1016/j.ccell.2015.09.001. PMID 26412324. 
  8. ↑ "c-Src-mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs". Molecular and Cellular Biology 22 (13): 4535–43. July 2002. doi:10.1128/mcb.22.13.4535-4543.2002. PMID 12052863. 
  9. ↑ "An RNA helicase, DDX1, interacting with poly(A) RNA and heterogeneous nuclear ribonucleoprotein K". The Journal of Biological Chemistry 277 (43): 40403–9. October 2002. doi:10.1074/jbc.M206981200. PMID 12183465. 
  10. ↑ 10.0 10.1 10.2 "Protein-protein interaction among hnRNPs shuttling between nucleus and cytoplasm". Journal of Molecular Biology 298 (3): 395–405. May 2000. doi:10.1006/jmbi.2000.3687. PMID 10772858. 
  11. ↑ "Functional interaction of Sam68 and heterogeneous nuclear ribonucleoprotein K". Oncogene 21 (47): 7187–94. October 2002. doi:10.1038/sj.onc.1205759. PMID 12370808. 
  12. ↑ "Sam68 RNA binding protein is an in vivo substrate for protein arginine N-methyltransferase 1". Molecular Biology of the Cell 14 (1): 274–87. January 2003. doi:10.1091/mbc.E02-08-0484. PMID 12529443. 
  13. ↑ "Identification of methylated proteins by protein arginine N-methyltransferase 1, PRMT1, with a new expression cloning strategy". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1591 (1–3): 1–10. August 2002. doi:10.1016/s0167-4889(02)00202-1. PMID 12183049. 

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: P61978 (Human Heterogeneous nuclear ribonucleoprotein K (HNRPK)) at the PDBe-KB.




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