Characterisation of the BRCT Domains of the Breast Cancer Susceptibility Gene Product BRCA1

Ekblad, Caroline; Wilkinson, Hannah; Schymkowitz, Joost; Rousseau, Frédéric; Freund, Stefan; Itzhaki, Laura S.

doi:10.1016/s0022-2836(02)00478-3

Cited by 44 publications

(75 citation statements)

References 34 publications

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“…3, inset and "Experimental Procedures"). Consistent with these findings, solvent denaturation measurements of the thermodynamic stability of the BRCT tandem domain indicates that M1775R destabilizes the BRCT fold by 5.0 kcal/mol at 20°C (36). Taken together, these results suggest that functional defects associated with BRCA1-M1775R may be attributed to destabilization of the BRCT domain at physiological temperatures.…”

Section: Structural Characterization Of a Brct Missense Variantsupporting

confidence: 73%

“…These movements are accomplished without the creation of large, energetically costly cavities within the hydrophobic core (33)(34)(35). The repacking of the core, however, in combination with instability created by hydrogen bonding changes and charge-charge repulsion of basic residues at the BRCT-BRCT interface may collectively help account for the 5 kcal/mol destabilization reported for the BRCT-M1775R protein (36).…”

Section: Structural Characterization Of a Brct Missense Variantmentioning

confidence: 99%

See 1 more Smart Citation

Structural Consequences of a Cancer-causing BRCA1-BRCT Missense Mutation

Williams

Glover

2003

Journal of Biological Chemistry

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The integrity of the carboxyl-terminal BRCT repeat region is critical for BRCA1 tumor suppressor function; however, the molecular details of how a number of clinically derived BRCT missense mutations affect BRCA1 function remain largely unknown. Here we assess the structural response of the BRCT tandem repeat domain to a well characterized, cancer-associated single amino acid substitution, Met-1775 3 Arg-1775. The structure of BRCT-M1775R reveals that the mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the two BRCT repeats contribute to the conformational instability of BRCT-M1775R. Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explain the pleiotropic molecular and genetic defects associated with the BRCA1-M1775R protein.Germ line mutations within the breast and ovarian cancer susceptibility gene BRCA1 predispose carriers to early onset breast and ovarian cancer, and it is estimated that ϳ5-10% of all breast cancers are caused by inheritance of dominant disease genes (1). Various lines of evidence suggest that the BRCA1 protein product is involved in the regulation of multiple nuclear functions including transcription, recombination, DNA repair, and checkpoint control (for reviews, see Refs. 2-4). BRCA1 is an 1863-amino acid nuclear phosphoprotein that includes an amino-terminal RING finger domain and two tandem carboxyl-terminal repeats, termed the BRCT domain. The importance of the conserved RING and BRCT domains to the tumor suppressor function of BRCA1 is demonstrated by the fact that the majority of known cancer-causing BRCA1 mutations localize to these domains (5-9).The extreme carboxyl-terminal region of BRCA1 contains two ϳ90 -100 amino acid sequence repeats called BRCT 1 (BRCA1 carboxyl-terminal) repeats that are the prototypical members of a protein fold superfamily that includes many proteins associated with DNA repair (10 -12). The recently determined x-ray crystal structures of the human (13) and rat (14) BRCA1 BRCT repeats provide a framework for the interpretation of BRCT mutations identified in patients from breast cancer screening programs. The two structurally similar BRCT repeats resemble the structures of the isolated BRCT domains from XRCC1 (15) and DNA ligase III (16) and are composed of a central four-stranded, parallel ␤-sheet flanked by a single ␣-helix on one side (␣2), with a pair of ␣-helices (␣1 and ␣3) and a short 3 10 -helix on the opposite side. The two repeats are connected by a relatively flexible linker and pack together in a specific, head-to-tail manner that is conserved not only between human and rat BRCA1 but also in the BRCT domain of the p53-interacting protein, 53BP1 (13,14). Several cancer-associated BRCT missense mutations (1, 6) have been characterized in functional detail. Two extensively studied variants, A1708E and M1775R,...

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Section: Structural Characterization Of a Brct Missense Variantsupporting

confidence: 73%

Section: Structural Characterization Of a Brct Missense Variantmentioning

confidence: 99%

Structural Consequences of a Cancer-causing BRCA1-BRCT Missense Mutation

Williams

Glover

2003

Journal of Biological Chemistry

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“…ApoE has been shown to undergo a twostage unfolding transition when treated with the chaotrope guanidine hydrochloride, with an unfolding intermediate appearing between 1-2 M ( 32 ). Modeling of the unfolding profi le to a three-state denaturation model can be used to calculate apparent values for the change in Gibbs energy during unfolding ( 35,42 ). The R145P mutant showed an unfolding profi le similar to that of wild-type apoE3, including the intermediate stage ( Fig.…”

Section: Ans Fl Uorescence Measurementsmentioning

confidence: 99%

Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy

Georgiadou

Stamatakis

Efthimiadou

et al. 2013

Journal of Lipid Research

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“…Mutation of Lys1702, either to alanine or the iso-steric methionine, also obliterated binding, verifying the importance of the side chain amino group for phospho-peptide recognition. 15,20 . We probed the ability of a large panel of these BRCA1 BRCT variants to bind biotinylated pSer-X-X-Phe peptides as described above (Figs.…”

Section: Rms Deviations Frommentioning

confidence: 99%

“…The M1775R mutation has previously been shown to cause a significant destabilization of the BRCA1 fold 14,20 .…”

Section: M1775rmentioning

confidence: 99%