The cancer-predisposing mutation C61G disrupts homodimer formation in the NH2-terminal BRCA1 RING finger domain - PubMed (original) (raw)
. 1998 Apr 3;273(14):7795-9.
doi: 10.1074/jbc.273.14.7795.
Affiliations
- PMID: 9525870
- DOI: 10.1074/jbc.273.14.7795
Free article
The cancer-predisposing mutation C61G disrupts homodimer formation in the NH2-terminal BRCA1 RING finger domain
P S Brzovic et al. J Biol Chem. 1998.
Free article
Abstract
The breast and ovarian cancer tumor suppressor gene, BRCA1, encodes for a Zn2+-binding RING finger motif located near the protein NH2 terminus. The RING finger motif is characterized by eight conserved Cys and His residues which form two Zn2+-binding sites termed Site I and Site II. We used limited proteolysis in conjunction with matrix-assisted laser desorption ionization time-of-flight mass spectroscopy to investigate the metal binding properties and to probe the solution structures of wild-type and mutant BRCA1 constructs that include the RING finger. Our results show that the RING finger motif is part of a larger proteolysis-resistant structural domain which encompasses the first 110 residues of BRCA1. Analytical gel-filtration chromatography and chemical cross-linking experiments demonstrate that the BRCA1 NH2-terminal domain readily homodimerizes in solution. The cancer-predisposing C61G mutation, which alters a conserved Zn2+-binding residue, abolishes metal binding to Site II of the RING finger motif, while Site I remains intact and functional. The C61G mutation also results in increased proteolytic susceptibility of the COOH-terminal portion of the NH2-terminal domain and perturbs the oligomerization properties of BRCA1.
Similar articles
- Structure of a BRCA1-BARD1 heterodimeric RING-RING complex.
Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE. Brzovic PS, et al. Nat Struct Biol. 2001 Oct;8(10):833-7. doi: 10.1038/nsb1001-833. Nat Struct Biol. 2001. PMID: 11573085 - BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions.
Brzovic PS, Meza JE, King MC, Klevit RE. Brzovic PS, et al. J Biol Chem. 2001 Nov 2;276(44):41399-406. doi: 10.1074/jbc.M106551200. Epub 2001 Aug 28. J Biol Chem. 2001. PMID: 11526114 - Substitution of aspartic acid with glutamic acid at position 67 of the BRCA1 RING domain retains ubiquitin ligase activity and zinc(II) binding with a reduced transition temperature.
Atipairin A, Canyuk B, Ratanaphan A. Atipairin A, et al. J Biol Inorg Chem. 2011 Feb;16(2):217-26. doi: 10.1007/s00775-010-0718-y. Epub 2010 Oct 22. J Biol Inorg Chem. 2011. PMID: 20967475 - Mechanisms of BRCA1 tumor suppression.
Silver DP, Livingston DM. Silver DP, et al. Cancer Discov. 2012 Aug;2(8):679-84. doi: 10.1158/2159-8290.CD-12-0221. Epub 2012 Jul 27. Cancer Discov. 2012. PMID: 22843421 Free PMC article. Review. - BRCA1 in breast and ovarian cancer predisposition.
Billack B, Monteiro AN. Billack B, et al. Cancer Lett. 2005 Sep 8;227(1):1-7. doi: 10.1016/j.canlet.2004.11.006. Epub 2004 Dec 13. Cancer Lett. 2005. PMID: 16051027 Review.
Cited by
- The emergence of Fanconi anaemia type S: a phenotypic spectrum of biallelic BRCA1 mutations.
Hughes T, Rose AM. Hughes T, et al. Front Oncol. 2023 Dec 11;13:1278004. doi: 10.3389/fonc.2023.1278004. eCollection 2023. Front Oncol. 2023. PMID: 38146508 Free PMC article. Review. - Conservation of transcriptional regulation by BRCA1 and BARD1 in Caenorhabditis elegans.
Thapa I, Vahrenkamp R, Witus SR, Lightle C, Falkenberg O, Sellin Jeffries MK, Klevit RE, Stewart MD. Thapa I, et al. Nucleic Acids Res. 2023 Mar 21;51(5):2108-2116. doi: 10.1093/nar/gkac877. Nucleic Acids Res. 2023. PMID: 36250637 Free PMC article. - RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage.
Krais JJ, Wang Y, Patel P, Basu J, Bernhardy AJ, Johnson N. Krais JJ, et al. Nat Commun. 2021 Aug 18;12(1):5016. doi: 10.1038/s41467-021-25346-4. Nat Commun. 2021. PMID: 34408138 Free PMC article. - SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation.
Minten EV, Kapoor-Vazirani P, Li C, Zhang H, Balakrishnan K, Yu DS. Minten EV, et al. Cell Rep. 2021 Mar 30;34(13):108921. doi: 10.1016/j.celrep.2021.108921. Cell Rep. 2021. PMID: 33789098 Free PMC article. - The antitumorigenic roles of BRCA1-BARD1 in DNA repair and replication.
Tarsounas M, Sung P. Tarsounas M, et al. Nat Rev Mol Cell Biol. 2020 May;21(5):284-299. doi: 10.1038/s41580-020-0218-z. Epub 2020 Feb 24. Nat Rev Mol Cell Biol. 2020. PMID: 32094664 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous