Molecular Chaperone Activity in Cellular Assembly Processes

Molecular chaperones are specialised proteins that assist the folding, stabilisation and assembly of other macromolecular components, ensuring the correct architecture of essential cellular machines. Through ATP-driven conformational cycles, chaperones prevent misfolding and aggregation, coordinate subunit interactions and shepherd nascent chains into functional complexes. The HSP70 and HSP90 systems form the core of this proteostatic network, often recruiting co-chaperones such as the R2TP complex to orchestrate the stepwise construction of multi-subunit assemblies including ribosomes, spliceosomes, RNA polymerases and kinase regulatory modules. These processes are fundamental to gene expression, signal transduction and metabolic control. Dysregulation of chaperone-mediated assembly is implicated in cancer, neurodegeneration and cardiomyopathy, and inhibitors targeting chaperone ATPases or adapter interactions are emerging as therapeutic strategies. Recent advances have elucidated structural mechanisms of client recognition, co-chaperone scaffolding and allosteric regulation, highlighting opportunities to modulate assembly pathways with precision.

Research from Nature Portfolio

Recent studies have characterised a reactivated embryonic ATPase as a modulator of tissue-specific assembly processes. Overexpression of this AAA+ ATPase in adult cardiomyocytes mitigates apoptosis, hypertrophy and fibrosis by promoting the assembly of Hippo-pathway signalling complexes, enhancing nuclear translocation of transcriptional co-activators and restoring regulatory networks. Deficiency in the same ATPase disrupts chaperone-mediated assembly of cell-cycle and survival complexes, underscoring its potential as a target for regenerative therapy.

High-resolution structural work has revealed how a metazoan co-chaperone provides a flexible scaffold for coupling HSP90 to diverse client proteins. Cryo-electron microscopy and biochemical analyses define a C-terminal domain that binds the ATPase ring of RUVBL2, while mobile TPR motifs on the opposite face recruit PIH1D1 and client adaptors. This dual-face architecture elucidates the modular assembly of quaternary chaperones and the mechanistic basis for bringing HSP90 into proximity with a spectrum of macromolecular clients.

Molecular Chaperone Activity in Cellular Assembly Processes publication trend

The graph below shows the total number of articles in molecular chaperone activity in cellular assembly processes across all publications each year (not limited to Nature Index journals).

Technical terms

Molecular chaperone: A protein that assists the folding, assembly or disassembly of other macromolecular structures without being part of the final assembly.

Co-chaperone: A partner protein that modulates chaperone activity, specificity or client recruitment, often by linking chaperones to substrate assemblies.

R2TP complex: A specialised HSP90 co-chaperone formed by RUVBL1/RUVBL2 AAA+ ATPases and the adaptors RPAP3 and PIH1D1, central to the assembly of large multi-protein machines.

AAA+ ATPase: A family of enzymes that use ATP hydrolysis to remodel proteins or complexes, driving conformational changes essential for assembly or disassembly.

Quaternary structure: The higher-order organisation arising from the assembly of multiple polypeptide subunits into a functional protein complex.

References

1. Expression of foetal gene Pontin is essential in protecting heart against pathological remodelling and cardiomyopathy. Nature Communications (2025).
2. RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex. Nature Communications (2018).
3. Molecular Signatures of CB-6644 Inhibition of the RUVBL1/2 Complex in Multiple Myeloma. International Journal of Molecular Sciences (2024).
4. The HSP90/R2TP Quaternary Chaperone Scaffolds Assembly of the TSC Complex. Journal of Molecular Biology (2024).
5. Unveiling the Role of Sorghum RPAP3 in the Function of R2TP Complex: Insights into Protein Assembly in Plants. Plants (2023).