Aug 2026· Proceedings of the National Academy of Sciences of the United States of America· Vol 123· 0 citations· 79 references
Medicine
TL;DR
An evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network from active repair to protection during stress is revealed, revealing an evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network from active repair to protection during stress.
Abstract
Significance Proteostasis depends on the coordinated actions of Hsp70 chaperones and their diverse J-domain protein (JDP) cochaperones, yet whether these act redundantly or carry distinct cellular functions has remained unresolved. Here, we uncover that despite being highly conserved, the J-domain exhibits subtle sequence-level differences across different JDP classes, which tune the affinity and specificity of JDPs for Hsp70 paralogs. As cellular stress increases, stress-inducible Hsp70s interact with an increasingly selective subset of JDPs, effectively releasing other broad-specificity JDPs to function as stand-alone chaperones, independently of Hsp70, protecting cellular clients from misfolding and aggregation. Together, these results reveal an evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network during stress from adenosine triphosphate-dependent repair to protective containment, ensuring robust proteostasis.
Intragenomic homologs are widespread, but their physiological roles are often masked by redundancy. Histone-like nucleoid structuring protein (H-NS), a nucleoid-associated protein in Gram-negative bacteria, typically coexists with homologs like StpA, whose functions are obscured by a lack of strong phenotypes. We demonstrate here that the interaction between H-NS and StpA fine-tunes the physico-chemical properties of nucleoid-associated compartments. Although H-NS forms dynamic condensates in vitro, StpA assembles into stable insoluble fibrils. However, together the two proteins form liquid-like droplets, whose fluidity and stability are tunable by their relative stoichiometry. By increasing the levels of StpA over H-NS, bacteria stabilize heterochromatin-associated compartments, thereby preserving gene repression and optimizing bacterial growth under stress. Structural differences at these proteins' dimerization sites help explain their distinct phase behaviors. Our findings reveal a paradigm in which intragenomic homologs that are positioned at the opposite ends of the phase spectrum can fine-tune subcellular organization to promote survival in fluctuating environments.
Jian Guan, Bikash R. Sahoo, Tyler S. Brant et al.· Molecules and Cells· 0 citations
How the regulatory networking of chaperones by cochaperones, particularly J domain proteins (JDPs; also called Hsp40 or DNAJ proteins), contributes to biocondensate formation and protein disaggregation to maintain proteostasis is discussed.
Gregory L. Blatch, Adrienne L. Edkins· 0 citations
A cross-kingdom synthesis of disorder-based chromatin regulation is developed, demonstrating that bacterial nucleoid-associated proteins, plant transcription factors, and mammalian chromatin regulators share a conserved charge-regulatory logic, mediated by PTM-dependent mechanisms that dynamically couple environmental signals with genome organization.
Sami N.Al Harake, Said Btadini, Abrar H. Qadri et al.· Biochemistry and Biophysics...· 0 citations
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
