Jane Dyson

Management of Hsp90-Dependent Protein Folding by Small Molecule Targeting the Aha1 Co-Chaperone

The core cytosolic Hsp90 chaperone/co-chaperone complex plays a critical role in proteostasis management of human health and disease. To identify novel compounds that alter the ability of the Hsp90 co-chaperone Aha1 to modulate the ATPase activity found in multiple folding diseases ranging from steroid hormone receptor (SHR) sensitive prostate cancer to tauopathies associated with neurodegenerative diseases, we employed a high throughput screening (HTS) assay to monitor selectively Aha1-stimulated Hsp90 (ASH) ATPase activity. The ASH assay identified SEW04784 (SEW), a small molecule that disrupts ASH activity without inhibiting the basal Hsp90 ATPase activity. NMR analysis reveals that SEW binds to the C-terminal domain of Aha1 to disrupt its asymmetric binding to Hsp90 leading to abrogation of its chaperoning activity of Hsp90. SEW exhibits therapeutic potential by blocking the transcriptional activity of prostate cancer (PCa) associated variants of the androgen receptor (AR) in a cell-based model of PCa. Additionally, SEW exhibits the ability to clear toxic, phosphorylated tau aggregated species associated with tauopathies. By not directly impacting the basal ATPase function of the abundant and ubiquitous Hsp90, SEW could provide a therapeutic approach for mitigation of client-specific proteostatic disease.

Greetings from Your New Editor-in-Chief

In my first editorial as Editor-in-Chief of Biophysical Journal, I want to emphasize the outstanding work our BJ team has done, and will continue to do, in producing a truly impactful scientific publication in which each issue contains a wealth of cutting-edge biophysics. I also wish to sing the praises of our outgoing Editor-in-Chief, Leslie (Les) M. Loew, who has done an amazing job implementing new initiatives, while constantly working to improve the quality and visibility of the journal and its component articles. He has been a wonderful mentor as I have prepared during the last 12 months to take on this job. We all owe Les a debt of gratitude for his dedication to the journal, and I know he will continue to promote and publish in BJ going forward.A high-quality journal should publish the best science. That means two things: first, the journal must attract excellent submissions; second, it must rigorously select the best submissions for publication. The first requirement depends on the journal’s reputation, which in turn depends on a number of factors: the reputation of the editor-in-chief and editorial board members, quality and fairness of review, turnaround time, editing quality, cost (page charges, color figures, etc.), and the perceived impact factor of the journal. An author’s decision to submit to a particular journal depends on these factors, as well as whether the journal publishes articles on subjects similar to that of the prospective submission, and a perception that the technical content of the manuscript is at a suitable level for the journal.Rigorous selection for quality depends on the editorial board of the journal and ultimately on the editor-in-chief. The editor-in-chief and the associate editors work together to create the culture of excellence and fairness that is a prerequisite for any successful journal. They recruit editorial board members, who are ratified by the Publications Committee. The editorial board is dynamic: the members’ terms are short (three years; renewable once) to ensure turnover. However, constant turnover means we must work constantly to integrate editorial board members into the journal’s culture. Our current editorial board has 135 members: is that the right size? Is there representation where there should be? Is it too large to ensure overall uniform high quality? This is something that will be evaluated on an ongoing basis.BJ has recently instituted sliding scales for reviewers to evaluate important criteria, and I believe this will add greatly to the review and evaluation process by focusing the attention of reviewers on issues that need to be addressed in the review. We also need to look at review turnaround times and what we can do to make our reviewers’ job easier, and give them recognition for quality, timely reviews.BJ remains on a very solid basis as a society-owned journal with an excellent reputation. BJ has continuously innovated to maintain and enhance efficiency, visibility, and relevance. The Society’s involvement is clearly a great strength, as evidenced by the special issues based on Biophysical Society (BPS) Thematic Meetings.What more can we do? BJ is a society journal, and we firmly believe that BJ serves the membership best by focusing on being the top journal in the field, the premier general biophysics journal that publishes the best biophysical research. To this end, we will continue to make use of new technologies and social media platforms. Les Loew has worked tirelessly to increase the journal’s presence in social media. This will be continued and amplified. We will develop interactive content on the BJ website and social media accounts. We will also expand the “Computational Tools” section to include “New Experimental Tools,” to showcase innovations in experimental biophysical methodology and, more generally, emphasize that biophysics is an evolving discipline and that BJ is an important catalyst in this development. The unabashed goal is the make the journal even more attractive as a venue for publishing the best research, such that BPS members look forward to publish their cutting-edge work in BJ.There is much to do, and I very much look forward to working with each of you, authors, reviewers, associate editors, and the members of the editorial board. Together we will strengthen the journal further by promoting the tradition of scientific excellence that has been the hallmark of Biophysical Journal.