Ribonuclease 4 Explained

Ribonuclease 4 is an enzyme that in humans is encoded by the RNASE4 gene.^{[1] [2]}

Function

The protein encoded by this gene belongs to the pancreatic ribonuclease family. 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.^[3] The human form of RNase 4 is an intracellular and plasma enzyme which was first isolated from colon adenocarcinoma cell line HT-29.^[4] It can be found in the pancreas, saliva, and the liver, displaying a similar distribution pattern to that of angiogenin (ANG). It plays an important role in mRNA cleavage and has marked specificity 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

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.

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 . Isolation and characterization of a human colon carcinoma-secreted enzyme with pancreatic ribonuclease-like activity . Biochemistry . 25 . 23 . 7255–7264 . November 1986 . 3467790 . 10.1021/bi00371a002 .
• Seno M, Futami J, Tsushima Y, Akutagawa K, Kosaka M, Tada H, Yamada H . Molecular cloning and expression of human ribonuclease 4 cDNA . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1261 . 3 . 424–426 . April 1995 . 7742370 . 10.1016/0167-4781(95)00040-n .
• Zhou HM, Strydom DJ . The amino acid sequence of human ribonuclease 4, a highly conserved ribonuclease that cleaves specifically on the 3' side of uridine . European Journal of Biochemistry . 217 . 1 . 401–410 . October 1993 . 8223579 . 10.1111/j.1432-1033.1993.tb18259.x .
• Egesten A, Dyer KD, Batten D, Domachowske JB, Rosenberg HF . Ribonucleases and host defense: identification, localization and gene expression in adherent monocytes in vitro . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1358 . 3 . 255–260 . October 1997 . 9366257 . 10.1016/S0167-4889(97)00081-5 . free .
• Terzyan SS, Peracaula R, de Llorens R, Tsushima Y, Yamada H, Seno M, Gomis-Rüth FX, Coll M . 6 . The three-dimensional structure of human RNase 4, unliganded and complexed with d(Up), reveals the basis for its uridine selectivity . Journal of Molecular Biology . 285 . 1 . 205–214 . January 1999 . 9878400 . 10.1006/jmbi.1998.2288 .
• Xu XR, Huang J, Xu ZG, Qian BZ, Zhu ZD, Yan Q, Cai T, Zhang X, Xiao HS, Qu J, Liu F, Huang QH, Cheng ZH, Li NG, Du JJ, Hu W, Shen KT, Lu G, Fu G, Zhong M, Xu SH, Gu WY, Huang W, Zhao XT, Hu GX, Gu JR, Chen Z, Han ZG . 6 . Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver . Proceedings of the National Academy of Sciences of the United States of America . 98 . 26 . 15089–15094 . December 2001 . 11752456 . 64988 . 10.1073/pnas.241522398 . 2001PNAS...9815089X . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .

Notes and References

1. Rosenberg HF, Dyer KD . Human ribonuclease 4 (RNase 4): coding sequence, chromosomal localization and identification of two distinct transcripts in human somatic tissues . Nucleic Acids Research . 23 . 21 . 4290–4295 . November 1995 . 7501448 . 307382 . 10.1093/nar/23.21.4290 .
2. Web site: Entrez Gene: RNASE4 ribonuclease, RNase A family, 4.
3. Li S, Sheng J, Hu JK, Yu W, Kishikawa H, Hu MG, Shima K, Wu D, Xu Z, Xin W, Sims KB, Landers JE, Brown RH, Hu GF . 6 . Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress . Angiogenesis . 16 . 2 . 387–404 . April 2013 . 23143660 . 3582744 . 10.1007/s10456-012-9322-9 .
4. Terzyan SS, Peracaula R, de Llorens R, Tsushima Y, Yamada H, Seno M, Gomis-Rüth FX, Coll M . 6 . The three-dimensional structure of human RNase 4, unliganded and complexed with d(Up), reveals the basis for its uridine selectivity . Journal of Molecular Biology . 285 . 1 . 205–214 . January 1999 . 9878400 . 10.1006/jmbi.1998.2288 .