Chem Bio Seminar- Prof. Stephen Fried (John Hopkins University)

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1315 Seminar Hall, North Tower
@ 11:00 am


Title: Intrinsically Disordered Regions Promote Protein Refoldability and Facilitate Retrieval from Biomolecular Condensates


Stephen Fried is a native of Kansas City. He received two S.B. degrees (2009) from MIT in chemistry and physics and completed his doctoral training at Stanford under the mentorship of Prof. S. G. Boxer in 2014. As a graduate student, Stephen’s research focused on understanding the physical principles underpinning enzymes’ catalytic power. From 2014 to 2018, Stephen was a Junior Research Fellow of King’s College and conducted research at the MRC Laboratory of Molecular Biology in Cambridge, United Kingdom. Stephen joined the Department of Chemistry at Johns Hopkins University in 2018, where he now holds appointments in the Departments of Biology and Biophysics. Stephen has been the recipient of an HFSP Young Investigator Award, the NIH Director’s New Innovator Award, a Cottrell Scholar, and a Camille-Dreyfus Teacher-Scholar ward.


Many eukaryotic proteins contain intrinsically disordered regions (IDRs) that intersperse globular folded domains, in contrast with bacterial proteins which are typically highly globular. Recent years have seen great progress in identifying biological functions associated with these elusive protein sequence: in specific cases, they mediate liquid-liquid phase separation, perform molecular recognition, or act as sensors to changes in the environment. Nevertheless, only a small number of IDRs have annotated functions6 despite their presence in 64% of yeast proteins, stimulating some to question what ‘general purpose’ they may serve. Here, by interrogating the refoldability of two fungal proteomes (Saccharomyces cerevisiae and Neurosporra crassa), we show that IDRs render their host proteins more refoldable from the denatured state, allowing them to cohere more closely to Anfinsen’s thermodynamic hypothesis. The data provide an exceptionally clear picture of which biophysical and topological characteristics enable refoldability. Moreover, we find that almost all yeast proteins that partition into stress granules during heat shock are refoldable, a finding that holds for other condensates such as P-bodies and the nucleolus. Finally, we find that the Hsp104 unfoldase is the principal actor in mediating disassembly of heat stress granules and that the efficiency with which condensed proteins are returned to the soluble phase is also well explained by refoldability. Hence, these studies establish spontaneous refoldability as an adaptive trait that endows proteins with the capacity to reform their native soluble structures following their extraction from condensates. Altogether, our results provide an intuitive model for the function of IDRs in many multidomain proteins and clarifies their relationship to the phenomenon of biomolecular condensation.

Keywords: Protein folding, mass spectrometry proteomics, intrinsically disordered regions, proteostasis

Host: Prof. Silvia Cavagnero