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An Error has occurred retrieving Wikidata item for infobox Ribonuclease 4 is an enzyme that in humans is encoded by the RNASE4 gene.

Function

The protein encoded by this gene belongs to the pancreatic ribonuclease superfamily. Secreted ribonucleases are the only enzyme family that is vertebrate-specific. Among the 13 members of this superfamily, ribonuclease 4 (RNase 4), is the most conserved gene across different vertebrate species. The human form of RNase 4 is an intracellular and plasma enzyme which was first isolated from colon adenocarcinoma cell line HT-29. It can also be found in the pancreas, saliva, and the liver, displaying a similar distribution pattern to that of angiogenin. It plays an important role in mRNA cleavage and is highly specific towards the 3' side of uridine nucleotides.

Alternative splicing results in two transcript variants encoding the same protein. RNase 4 is co-expressed and shares the same promoter with angiogenin (ANG), another member of this superfamily. Each gene splices to a unique downstream exon that contains its complete coding region. RNase 4 has also been studied in its involvement with amyotrophic lateral sclerosis (ALS), a nervous system disease, due to its similarity with ANG which has been associated with ALS pathogenesis.

Structure

Shown is a PyMol image of the ribonuclease 4 dimer, blue, with its preferred substrate uridine, white, in the active site.

RNase 4 features a unique structure compared to its homologous enzymes in the superfamily. It contains 119 amino acid residues making it the shortest known human RNase and contains no N-glycosylation sites. RNase 4 displays an α + β type polypeptide chain folding and a V-shape with the active site cleft in the middle. It contains three α-helices and four β -strands while the secondary structures are connected by six loops. There are four disulfide bridges located throughout the structure that connect the α-helices, β -strands, and loops. The overall structure of RNase 4 is similar to its homologous enzyme RNase A, EDN, and angiogenin.

The three residues Phe42, Arg101, Thr44 (shown in blue) contribute to the specificity of ribonuclease 4 by recognizing the uridine substrate (shown in white).

A shorter C terminus is a unique feature of RNase 4 which places the carboxy terminus in the pyrimidine recognition site which results in RNase 4 unique specificity. The pyrimidine recognition site is where there are major difference compared to its homologous enzymes. It contains an arginine residue at position 101, a phenylalanine reside at 42, and a threonine residue at 44. These residues contribute to the ribonuclease 4 specificity and are adapted to recognize a uridine-type base over cytidine-containing substrates.

Further reading

• Shapiro R, Fett JW, Strydom DJ, Vallee BL (1987). "Isolation and characterization of a human colon carcinoma-secreted enzyme with pancreatic ribonuclease-like activity". Biochemistry. 25 (23): 7255–64. doi:10.1021/bi00371a002. PMID 3467790.
• Seno M, Futami J, Tsushima Y, et al. (1995). "Molecular cloning and expression of human ribonuclease 4 cDNA". Biochim. Biophys. Acta. 1261 (3): 424–6. doi:10.1016/0167-4781(95)00040-n. PMID 7742370.
• Zhou HM, Strydom DJ (1993). "The amino acid sequence of human ribonuclease 4, a highly conserved ribonuclease that cleaves specifically on the 3' side of uridine". Eur. J. Biochem. 217 (1): 401–10. doi:10.1111/j.1432-1033.1993.tb18259.x. PMID 8223579.
• Egesten A, Dyer KD, Batten D, et al. (1997). "Ribonucleases and host defense: identification, localization and gene expression in adherent monocytes in vitro". Biochim. Biophys. Acta. 1358 (3): 255–60. doi:10.1016/S0167-4889(97)00081-5. PMID 9366257.
• Terzyan SS, Peracaula R, de Llorens R, et al. (1999). "The three-dimensional structure of human RNase 4, unliganded and complexed with d(Up), reveals the basis for its uridine selectivity". J. Mol. Biol. 285 (1): 205–14. doi:10.1006/jmbi.1998.2288. PMID 9878400.
• Xu XR, Huang J, Xu ZG, et al. (2002). "Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver". Proc. Natl. Acad. Sci. U.S.A. 98 (26): 15089–94. doi:10.1073/pnas.241522398. PMC 64988. PMID 11752456.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Rual JF, Venkatesan K, Hao T, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.

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