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Abstract Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated.

Abstract Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor signaling. The structures of homodimeric PAPP-A in complex with IGFBP5 anchor peptide, and inhibitor proteins STC2 and proMBP have been recently reported. Here, we present the single-particle cryo-EM structure of the monomeric, N-terminal LG, MP, and the M1 domains (with the exception of LNR1/2) of human PAPP-A2 to 3.13 Å resolution. Our structure together with functional studies provides insight into a previously reported patient mutation that inactivates PAPP-A2 in a distal region of the protein. Using a combinational approach, we suggest that PAPP-A2 recognizes IGFBP5 in a similar manner as PAPP-A and show that PAPP-A2 cleaves IGFBP5 less efficiently due to differences in the M2 domain. Overall, our studies characterize the cleavage mechanism of IGFBP5 by PAPP-A2 and shed light onto key differences with its paralog PAPP-A.

IntroductionSleep problems frequently arise during adolescence and early adulthood and may contribute to the onset of depression. However, few sleep health instruments have been developed for use in student populations. Here, we developed a brief sleep health questionnaire for identifying adolescents and university students with sleep problems who may be at risk of depression.MethodsIn Study 1, sleep survey data in adolescents (n = 1,733) were analyzed by best-subsets regression to identify the strongest predictors of self-reported depression symptoms: sleep quality, daytime sleepiness, self-rated health, frequency of staying up until 3:00 am, school day sleep latency, and gender. A 6-item Sleep Health And Wellness Questionnaire (SHAWQ) was developed using these items. Students were categorized into good, fair, and bad sleep health groups based on their composite SHAWQ scores. In Study 2, the SHAWQ was tested in adolescents (n = 1,777) for associations with depression symptoms and excessive daytime sleepiness. In Study 3, the SHAWQ was tested in university students (n = 2,040) for convergent validity with instruments for measuring sleep quality and insomnia severity, and for associations with major depressive disorder symptoms and anxiety disorder symptoms. Test-retest reliability was determined in a subset of 407 students who re-took the SHAWQ several weeks later. In Study 4, we tested whether SHAWQ scores in university freshmen (cohort 1, n = 1,529; cohort 2, n = 1,488) were prospectively associated with grade point average (GPA) over their first year.ResultsAcross studies, SHAWQ scores were associated with higher depression and anxiety scores, excessive daytime sleepiness, lower sleep quality scores, and higher insomnia severity scores, demonstrating good convergent validity. Associations of SHAWQ scores with depression symptoms were stronger compared with anxiety symptoms. SHAWQ scores showed moderate test-retest reliability. Large effect sizes were observed for bad vs. good sleep health for all sleep and mental health variables. In both cohorts of university freshmen, students with bad sleep health had lower academic performance based on their GPA and percentile rank.ConclusionOur findings suggest that the SHAWQ could be used to screen for students in their teens and twenties with bad sleep health who would benefit from counseling for sleep and mental health.

PAPP-A substrate selectivity underlies the tight regulation of IGF signaling. Here, the authors report cryo-EM structures of dimeric PAPP-A in its substrate-free form and in complex with a peptide substrate, which combined with biochemical assays provide a mechanism for PAPP-A substrate binding and selectivity.

The current research tested the hypothesis that individuals engaged in long-term efforts to limit food intake (e.g., individuals with high eating restraint) would have reduced capacity to regulate eating when self-control resources are limited. In the current research, body mass index (BMI) was used as a proxy for eating restraint based on the assumption that individuals with high BMI would have elevated levels of chronic eating restraint. A preliminary study (Study 1) aimed to provide evidence for the assumed relationship between eating restraint and BMI. Participants (N = 72) categorized into high or normal-range BMI groups completed the eating restraint scale. Consistent with the hypothesis, results revealed significantly higher scores on the weight fluctuation and concern for dieting subscales of the restraint scale among participants in the high BMI group compared to the normal-range BMI group. The main study (Study 2) aimed to test the hypothesized interactive effect of BMI and diminished self-control resources on eating behavior. Participants (N = 83) classified as having high or normal-range BMI were randomly allocated to receive a challenging counting task that depleted self-control resources (ego-depletion condition) or a non-depleting control task (no depletion condition). Participants then engaged in a second task in which required tasting and rating tempting cookies and candies. Amount of food consumed during the taste-and-rate task constituted the behavioral dependent measure. Regression analyses revealed a significant interaction effect of these variables on amount of food eaten in the taste-and-rate task. Individuals with high BMI had reduced capacity to regulate eating under conditions of self-control resource depletion as predicted. The interactive effects of BMI and self-control resource depletion on eating behavior were independent of trait self-control. Results extend knowledge of the role of self-control in regulating eating behavior and provide support for a limited-resource model of self-control.