Thermal denaturation of the BRCT tandem repeat region of human tumour suppressor gene product BRCA1.
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.
Pyrpassopoulos
Serapion
S
National Centre for Scientific Research Demokritos, Patriarchou Gregoriou St., 153 10 Aghia Paraskevi, Greece.
Ladopoulou
Angela
A
Vlassi
Metaxia
M
Papanikolau
Yannis
Y
Vorgias
Constantinos E
CE
Yannoukakos
Drakoulis
D
Nounesis
George
G
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
D019313:BRCA1 Protein