Impact of BRCA1 BRCT Domain Missense Substitutions on Phosphopeptide Recognition

The BRCA1 BRCT domain binds pSer-x-x-Phe motifs in partner proteins to regulate the cellular response to DNA damage. Approximately 120 distinct missense variants have been identified in the BRCA1 BRCT through breast cancer screening, and several of these have been linked to an increased cancer risk. Here we probe the structures and peptide-binding activities of variants that affect the BRCA1 BRCT phosphopeptide-binding groove. The results obtained from the G1656D and T1700A variants illustrate the role of Ser1655 in pSer recognition. Mutations at Arg1699 (R1699W and R1699Q) significantly reduce peptide binding through loss of contacts to the main chain of the Phe(+3) residue and, in the case of R1699W, to a destabilization of the BRCT fold. The R1835P and E1836K variants do not dramatically reduce peptide binding, in spite of the fact that these mutations significantly alter the structure of the walls of the Phe(+3) pocket

A comparison of daily physical activity profiles between adults with severe asthma and healthy controls.

Severe asthma is associated with a substantial burden of disease including premature death and reduced quality adjusted life years [1]. Care in specialist centres is associated with reduced exacerbation rates and healthcare utilisation, but at the cost of increased use of systemic steroids and increased body mass index (BMI) [2]. Common co-comorbidities such as metabolic syndrome and type 2 diabetes are associated with low levels of moderate-vigorous physical activity (MVPA) [3]. Guidelines recommend that adults accumulate either =150 minutes of moderate intensity activity or =75 minutes of vigorous intensity activity per week, accumulated in bouts of any length [4]. Adults with severe asthma may avoid MVPA due to negative expectations and fear-avoidance beliefs [5]. A few small studies have reported that daily step count and time spent in MVPA may be reduced in adults with severe asthma compared to controls [6–8]. However, results are conflicting when physical activity levels are adjusted for confounders such as age, gender, obesity and smoking [7]. Furthermore, adults with severe asthma have reduced health-related quality of life (HRQoL) but whether physical activity levels impact on HRQoL is unknown [9].</p