title: Thermal denaturation of the BRCT tandem repeat region of human tumour suppressor gene product BRCA1.
abstract: Reduced stability of the tandem BRCT domains of human BReast CAncer 1 (BRCA1) due to missense mutations may be critical for loss of function in DNA repair and damage-induced checkpoint control. In the present thermal denaturation study of the BRCA1 BRCT region, high-precision differential scanning calorimetry (DSC) and circular dichroism (CD) spectroscopy provide evidence for the existence of a denatured state that is structurally very similar to the native. Consistency between theoretical structure-based estimates of the enthalpy (DeltaH) and heat capacity change (DeltaCp) and the calorimetric results is obtained when considering partial thermal unfolding contained in the region of the conserved hydrophobic pocket formed at the interface of the two BRCT repeats. The structural integrity of this region has been shown to be crucial for the interaction of BRCA1 with phosphorylated peptides. In addition, cancer-causing missense mutations located at the inter-BRCT-repeat interface have been linked to the destabilization of the tandem BRCT structure.
authors.affiliation: National Centre for Scientific Research Demokritos, Patriarchou Gregoriou St., 153 10 Aghia Paraskevi, Greece.
authors.forename: Serapion
authors.initials: S
authors.lastname: Pyrpassopoulos
authors.forename: Angela
authors.initials: A
authors.lastname: Ladopoulou
authors.forename: Metaxia
authors.initials: M
authors.lastname: Vlassi
authors.forename: Yannis
authors.initials: Y
authors.lastname: Papanikolau
authors.forename: Constantinos E
authors.initials: CE
authors.lastname: Vorgias
authors.forename: Drakoulis
authors.initials: D
authors.lastname: Yannoukakos
authors.forename: George
authors.initials: G
authors.lastname: Nounesis
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics*; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D004249:DNA Damage; D004260:DNA Repair; D004355:Drug Stability; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D020080:Tandem Repeat Sequences; D013696:Temperature; D013997:Time Factors
chemical_list: D019313:BRCA1 Protein