Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress.

Intragenomic homologs with distinct phase behaviors broaden the range of cellular stress responses.

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.

Chaperoning through time - defining DNAJA2 co-chaperone client selectivity via pulse-SILAC and BioID

The Central Role and Therapeutic Potential of Cochaperone Networking of Chaperones in the Regulation of Biocondensates

Revisiting the Small Heat Shock Protein Family in Caenorhabditis elegans: Insights from Phylogenetic, Structural, and Functional Analyses

Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones with diverse cellular functions. Here, we systematically reassessed two subfamilies of sHSPs in C. elegans by integrating evolutionary, genomic, and biophysical analyses. We report analysis of 18 α-crystallin domain-containing sHSPs, including two previously uncharacterized HSP-16-like proteins (designated hsp-16.31 & hsp-16.32 ). This analysis also supports the inclusion of two other proteins, ZK1128.7 and Y55F3BR.6 , as additional members of the C. elegans sHSP family. Comparative analyses reveal substantial diversity in tissue expression, intrinsic disorder, and liquid-liquid phase separation (LLPS) propensity, highlighting extensive functional specialization within the family.

Beyond the structure-function paradigm: A comprehensive review of intrinsically disordered proteins

Intrinsically disordered proteins (IDPs) and regions (IDRs) challenge the classical structure–function paradigm by fulfilling essential biological roles in the absence of a stable three-dimensional fold. Rather than occupying fixed conformations, IDPs exist as dynamic ensembles that enable high-specificity, low-affinity interactions, multivalent regulatory functions, and context-dependent binding across diverse cellular environments. This conformational plasticity underlies their central roles in signaling, transcriptional regulation, chromatin organization, and the assembly of membrane-less organelles through liquid–liquid phase separation (LLPS). The present review offers several conceptual contributions. First, we develop a cross-kingdom synthesis of disorder-based chromatin regulation, 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. Second, we integrate mechanistically related but frequently siloed disease pathways, including mitophagy dysfunction, oxidative stress signaling, neuroinflammation, and aberrant phase separation, into a unified framework linking IDP conformational dysregulation to neurodegeneration and cancer. Third, we highlight underexplored regulatory dimensions of IDP biology, including proline isomerization and ubiquitylation-driven condensate formation, that influence conformational ensembles and signaling outputs in ways not captured by conventional structural approaches. Finally, we critically evaluate recent advances in AI-assisted disorder prediction and hybrid experimental-computational ensemble characterization, emphasizing both their transformative potential and current limitations. Dysregulation of IDPs underlies a broad spectrum of human pathologies, and we discuss the emerging opportunities and persistent challenges in targeting these conformationally dynamic proteins therapeutically, including through PROTAC-based degraders, condensate modulators, and ensemble-based drug screening strategies.

Weak interactions drive selective proteome demixing and tune the differential response to environmental perturbations