Intrinsically Disordered N-terminal Domain (NTD) of p53 Interacts with Mitochondrial PTP Regulator Cyclophilin D.

Mitochondrial permeability transition pore (mPTP) plays crucial roles in cell death in a variety of diseases, including ischemia/reperfusion injury in heart attack and stroke, neurodegenerative conditions, and cancer. To date, cyclophilin D is the only confirmed component of mPTP. Under stress, p53 can translocate into mitochondria and interact with CypD, triggering necrosis and cell growth arrest. However, the molecular details of p53/CypD interaction are still poorly understood. Previously, several studies reported that p53 interacts with CypD through its DNA-binding domain (DBD). However, using surface plasmon resonance (SPR), we found that both NTD-DBD, NTD and NTD (1-70) bind to CypD at ∼µM KD. In solution NMR, NTD binds CypD with µM affinity and mimics the pattern of FLp53 binding in chemical shift perturbation. In contrast, neither solution NMR nor fluorescence anisotropy detected DBD binding to CypD. Thus, instead of DBD, NTD is the major CypD binding site on p53. NMR titration and MD simulation revealed that NTD binds CypD with broad and dynamic interfaces dominated by electrostatic interactions. NTD 20-70 was further identified as the minimal binding region for CypD interaction, and two NTD fragments, D1 (residues 22-44) and D2 (58-70), can each bind CypD with mM affinity. Our detailed biophysical characterization of the dynamic interface between NTD and CypD provides novel insights on the p53-dependent mPTP opening and drug discovery targeting NTD/CypD interface in diseases.

Perceived Feasibility, Acceptability, and Cultural Adaptation for a Mental Health Intervention in Rural Haiti.

Mental healthcare is largely unavailable throughout Haiti, particularly in rural areas. The aim of the current study is to explore perceived feasibility, acceptability, and effectiveness of potential culturally adapted interventions to improve mental health among Haitian women. The study used focus group discussions (n = 12) to explore five potential interventions to promote mental health: individual counseling, income-generating skills training, peer support groups, reproductive health education, and couples' communication training. Findings indicate that individual counseling, support group, and skills training components were generally anticipated to be effective, acceptable, and feasible by both male and female participants. That being said, participants expressed doubts regarding the acceptability of the couples' communication training and reproductive health education due to: a perceived lack of male interest, traditional male and female gender roles, lack of female autonomy, and misconceptions about family planning. Additionally, the feasibility, effectiveness, and acceptability of the components were described as dependent on cost, proximity to participants, and inclusion of a female health promoter that is known in the community. Given the lack of research on intervention approaches in Haiti, particularly those targeting mental health, this study provides a foundation for developing prevention and treatment approaches for mental distress among Haitian women.