| Structural highlights
Function
[RBM5_HUMAN] Component of the spliceosome A complex. Regulates alternative splicing of a number of mRNAs. May modulate splice site pairing after recruitment of the U1 and U2 snRNPs to the 5' and 3' splice sites of the intron. May both positively and negatively regulate aopotosis by regulating the alternative splicing of several genes involved in this process, including FAS and CASP2/caspase-2. In the case of FAS, promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis. In the case of CASP2/caspase-2, promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
The RNA binding motif protein 5 (RBM5), also known as Luca15 or H37, is a component of prespliceosomal complexes that regulates the alternative splicing of several mRNAs, such as Fas and caspase-2. The RBM5 gene is located at the 2p21.3 chromosomal region, which is strongly associated with lung cancer and many other cancers. Both increased and decreased levels of RBM5 can play a role in tumor progression. In particular, downregulation of rbm5 is involved in lung cancer and other cancers upon Ras activation, and, also, represents a molecular signature associated with metastasis in various solid tumors. On the other hand, upregulation of RBM5 occurs in breast and ovarian cancer. Moreover, RBM5 was also found to be involved in the early stage of the HIV-1 viral cycle, representing a potential target for the treatment of the HIV-1 infection. While the molecular basis for RNA recognition and ubiquitin interaction has been structurally characterized, small molecules binding this zinc finger (ZF) domain that might contribute to characterizing their activity and to the development of potential therapeutic agents have not yet been reported. Using an NMR screening of a fragment library we identified several binders and the complex of the most promising one, compound 1, with the RBM5 ZF1 was structurally characterized in solution. Interestingly, the binding mechanism reveals that 1 occupies the RNA binding pocket and is therefore able to compete with the RNA to bind RBM5 RanBP2-type ZF domain, as indicated by NMR studies.
Targeting Zinc Finger Domains with Small Molecules: Solution Structure and Binding Studies of the RanBP2-Type Zinc Finger of RBM5.,Farina B, Fattorusso R, Pellecchia M Chembiochem. 2011 Dec 16;12(18):2837-45. doi: 10.1002/cbic.201100582. PMID:22162216[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sutherland LC, Edwards SE, Cable HC, Poirier GG, Miller BA, Cooper CS, Williams GT. LUCA-15-encoded sequence variants regulate CD95-mediated apoptosis. Oncogene. 2000 Aug 3;19(33):3774-81. PMID:10949932 doi:http://dx.doi.org/10.1038/sj.onc.1203720
- ↑ Mourtada-Maarabouni M, Sutherland LC, Williams GT. Candidate tumour suppressor LUCA-15 can regulate multiple apoptotic pathways. Apoptosis. 2002 Oct;7(5):421-32. PMID:12207175
- ↑ Mourtada-Maarabouni M, Sutherland LC, Meredith JM, Williams GT. Simultaneous acceleration of the cell cycle and suppression of apoptosis by splice variant delta-6 of the candidate tumour suppressor LUCA-15/RBM5. Genes Cells. 2003 Feb;8(2):109-19. PMID:12581154
- ↑ Rintala-Maki ND, Sutherland LC. LUCA-15/RBM5, a putative tumour suppressor, enhances multiple receptor-initiated death signals. Apoptosis. 2004 Jul;9(4):475-84. PMID:15192330 doi:http://dx.doi.org/10.1023/B:APPT.0000031455.79352.57
- ↑ Oh JJ, Razfar A, Delgado I, Reed RA, Malkina A, Boctor B, Slamon DJ. 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Res. 2006 Apr 1;66(7):3419-27. PMID:16585163 doi:http://dx.doi.org/66/7/3419
- ↑ Bonnal S, Martinez C, Forch P, Bachi A, Wilm M, Valcarcel J. RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell. 2008 Oct 10;32(1):81-95. doi: 10.1016/j.molcel.2008.08.008. PMID:18851835 doi:http://dx.doi.org/10.1016/j.molcel.2008.08.008
- ↑ Fushimi K, Ray P, Kar A, Wang L, Sutherland LC, Wu JY. Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5. Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15708-13. doi:, 10.1073/pnas.0805569105. Epub 2008 Oct 7. PMID:18840686 doi:http://dx.doi.org/10.1073/pnas.0805569105
- ↑ Farina B, Fattorusso R, Pellecchia M. Targeting Zinc Finger Domains with Small Molecules: Solution Structure and Binding Studies of the RanBP2-Type Zinc Finger of RBM5. Chembiochem. 2011 Dec 16;12(18):2837-45. doi: 10.1002/cbic.201100582. PMID:22162216 doi:10.1002/cbic.201100582
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