Yeast Cadmium Factor 1 (Ycf1) sequesters heavy metals and glutathione into the vacuole to counter cell stress. Ycf1 belongs to the ATP binding cassette C-subfamily (ABCC) of transporters, many of which are regulated by phosphorylation on intrinsically-disordered domains. The regulatory mechanism of phosphorylation is still poorly understood. Here, we report two cryo-EM structures of Ycf1 at 3.4 Å and 4.0 Å resolution in inward-facing open conformations that capture previously unobserved ordered states of the intrinsically disordered regulatory domain (R-domain). R-domain phosphorylation is clearly evident and induces a topology promoting electrostatic and hydrophobic interactions with Nucleotide Binding Domain 1 (NBD1) and the Lasso motif. These interactions stay constant between the structures and are related by rigid body movements of the NBD1/R-domain complex. Biochemical data further show R-domain phosphorylation reorganizes the Ycf1 architecture and is required for maximal ATPase activity. Together, we provide insights into how R-domains control ABCC transporter activity.
Background Childhood abuse and intimate partner violence have each been associated with migraine headaches in previous studies, but these associations have not been explored among pregnant women. Objective To examine the independent and joint associations of childhood abuse and intimate partner violence with migraine among pregnant women. Methods A cross-sectional study was conducted among a cohort of 2,970 pregnant women attending prenatal clinics in Lima, Peru. History of childhood abuse (i.e., physical or sexual abuse) was assessed using the Childhood Physical and Sexual Abuse Questionnaire. Intimate partner violence (IPV) was assessed using the World Health Organization questionnaire. Migraine classification (including migraine and probable migraine) was based on International Classification of Headache Disorders (ICHD)-III beta criteria. Multivariable logistic regression analyses were performed to estimate odd ratios (OR) and 95% confidence intervals (95% CI). Results The prevalence of any migraine was 33.5% while approximately 70% of participants reported a history of childhood abuse and 36.7% a history of IPV. Women with a history of any childhood abuse had a 38% increased odds of any migraine compared to women with no history of childhood abuse (OR=1.38; 95% CI 1.15-1.64). The odds of migraine increased with increasing numbers of experienced childhood abuse events (Ptrend <0.001). Additionally, after adjusting for confounders women with a history of IPV had a 43% increased odds of any migraine as compared to women without intimate partner violence (OR=1.43; 95%CI 1.02-2.02). Women with a joint positive history of childhood abuse and IPV as compared with the reference group, had a 88% increased odds of migraine (aOR=1.88, 95%CI: 1.51-2.35). Conclusion Childhood abuse and IPV are associated with increased odds of migraine in pregnant women. Our findings highlight the importance of screening for abuse among pregnant migraineurs to help guide treatment strategies.
Yeast Cadmium Factor-1 (Ycf1) sequesters heavy metals and glutathione into the vacuole to counter cell stress. Ycf1 belongs to the ATP binding cassette C-subfamily (ABCC) of transporters, many of which are regulated by phosphorylation on intrinsically disordered domains. The regulatory mechanism of phosphorylation is still poorly understood. Here, we report two cryo-EM structures of Ycf1 at 3.4Å and 4.0Å in distinct inward-facing open conformations capturing a previously unobserved ordered state of the intrinsically disordered regulatory domain (R-domain). R-domain phosphorylation is clearly evident and induces a topology promoting electrostatic and hydrophobic interactions with Nucleotide Binding Domain 1 (NBD1) and the lasso domain. These interactions stay constant between the structures and are related by rigid body movements of the NBD1/R-domain complex. Biochemical data further show R-domain phosphorylation reorganizes the Ycf1 architecture and is required for maximal ATPase activity. Together, we provide long-sought after insights into how R-domains control ABCC transporter activity.
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