Graphical Abstract Highlights d SDS22 and I3 form a transient inactive complex with PP1 during PP1 biogenesis d SDS22-PP1-I3 disassembly by the p97 AAA-ATPase allows holoenzyme formation d Direct binding of I3 by the SEP domain of the p37 adapter mediates p97 recruitment d Disassembly involves ATP-driven pulling of I3 into the channel of the p97 hexamer Correspondence hemmo.meyer@uni-due.de In BriefWeith et al. demonstrate that newly synthesized PP1 is first held in an inactive complex by SDS22 and inhibitor-3 that needs to be disassembled by the p97 AAA-ATPase to promote exchange to substrate specifiers. Disassembly involves direct interaction of the p37 adapter with inhibitor-3, followed by its ATP-driven unfolding. SUMMARYThe functional diversity of protein phosphatase-1 (PP1), with its countless substrates, relies on the ordered assembly of alternative PP1 holoenzymes.Here, we show that newly synthesized PP1 is first held by its partners SDS22 and inhibitor-3 (I3) in an inactive complex, which needs to be disassembled by the p97 AAA-ATPase to promote exchange to substrate specifiers. Unlike p97-mediated degradative processes that require the Ufd1-Npl4 ubiquitin adapters, p97 is targeted to PP1 by p37 and related adapter proteins. Reconstitution with purified components revealed direct interaction of the p37 SEP domain with I3 without the need for ubiquitination, and ATP-driven pulling of I3 into the central channel of the p97 hexamer, which triggers dissociation of I3 and SDS22. Thus, we establish regulatory ubiquitin-independent protein complex disassembly as part of the functional arsenal of p97 and define an unanticipated essential step in PP1 biogenesis that illustrates the molecular challenges of ordered subunit exchange. and helped with supervision of the project. J.H. generated adapter cell lines. I.P. and A.M. generated and provided baculoviruses coding for PP1 components. F.K. and M. Kaiser performed mass spectrometry measurements. J.d.P.G. and M.B. advised and analyzed data. H.M. conceived and supervised the project and wrote the manuscript. DECLARATION OF INTERESTSThe authors declare no competing interests.

With respect to inconsistent findings on the interplay between usability and aesthetics, the current paper aimed to further examine the effect of these variables on perceived qualities of a mobile phone prototype. An experiment with four versions of the prototype varying on two factors, (1) usability (high versus low) and (2) aesthetics (high versus low), was conducted with perceived usability and perceived beauty, as well as hedonic experience and the system's appeal as dependent variables. Participants of the experiment ( = 88) were instructed to complete four typical tasks with the prototype before assessing its quality. Results showed that the mobile phone's aesthetics does not affect its perceived usability, either directly or indirectly. Instead, results revealed an effect of usability on perceived beauty, which supports the "what is usable is beautiful" notion instead of "what is beautiful is usable. " Furthermore, effects of aesthetics and of usability on hedonic experience in terms of endowing identity and appeal were found, indicating that both instrumental (usability) and noninstrumental (beauty) qualities contribute to a positive user experience.

The ubiquitin-directed AAA-ATPase VCP/p97 facilitates degradation of damaged or misfolded proteins in diverse cellular stress response pathways. Resolving the complexity of its interactions with partner and substrate proteins and understanding its links to stress signaling is therefore a major challenge. Here, we used affinity-purification SWATH mass spectrometry (AP-SWATH) to identify proteins that specifically interact with the substrate-trapping mutant, p97-E578Q. AP-SWATH identified differential interactions over a large detection range from abundant p97 cofactors to pathway-specific partners and individual ligases such as RNF185 and MUL1 that were trapped in p97-E578Q complexes. In addition, we identified various substrate proteins and candidates including the PP1 regulator CReP/PPP1R15B that dephosphorylates eIF2α and thus counteracts attenuation of translation by stress-kinases. We provide evidence that p97 with its Ufd1-Npl4 adapter ensures rapid constitutive turnover and balanced levels of CReP in unperturbed cells. Moreover, we show that p97-mediated degradation, together with a reduction in CReP synthesis, is essential for timely stress-induced reduction of CReP levels and, consequently, for robust eIF2α phosphorylation to enforce the stress response. Thus, our results demonstrate that p97 not only facilitates bulk degradation of misfolded proteins upon stress, but also directly modulates the integrated stress response at the level of signaling.

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Background To be able to make informed choices based on their individual preferences, patients need to be adequately informed about treatment options and their potential outcomes. This implies that studies measure the effects of care based on parameters that are relevant to patients. In a previous scoping review, we found a wide variety of supposedly patient-relevant parameters that equally addressed processes and outcomes of care. We were unable to identify a consistent understanding of patient relevance and therefore aimed to develop an empirically based concept including a generic set of patient-relevant parameters. As a first step we evaluated the process and outcome parameters identified in the scoping review from the patients’ perspective. Methods We conducted a cross-sectional survey among German general practice patients. Ten research practices of Witten/Herdecke University supported the study. During a two-week period in the fall of 2020, patients willing to participate self-administered a short questionnaire. It evaluated the relevance of the 32 parameters identified in the scoping review on a 5-point Likert scale and offered a free-text field for additional parameters. These free-text answers were inductively categorized by two researchers. Quantitative data were analyzed using descriptive statistics. Bivariate analyses were performed to determine whether there are any correlations between rating a parameter as highly relevant and patients’ characteristics. Results Data from 299 patients were eligible for analysis. All outcomes except ‘sexuality’ and ‘frequency of healthcare service utilization’ were rated important. ‘Confidence in therapy’ was rated most important, followed by ‘prevention of comorbidity’ and ‘mobility’. Relevance ratings of five parameters were associated with patients’ age and gender, but not with their chronic status. The free-text analysis revealed 15 additional parameters, 12 of which addressed processes of care, i.e., ‘enough time in physician consultation’. Conclusion Patients attach great value to parameters addressing processes of care. It appears as though the way in which patients experience the care process is not less relevant than what comes of it. Relevance ratings were not associated with chronic status, but few parameters were gender- and age-related. Trial registration Core Outcome Measures in Effectiveness Trials Initiative, registration number: 1685.

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