Nascent and partially folded proteins

Nascent and partially folded proteins are polypeptides in the process of being synthesized by the ribosome or those that have not yet achieved their native, functional three-dimensional conformation. These intermediates are highly dynamic and sensitive, requiring the assistance of molecular chaperones, such as the HSP70 and HSP90 families, to prevent non-specific aggregation and ensure correct folding (Hartl et al., 2011, Nature). In various pathologies, including neurodegenerative diseases like Alzheimer's and Parkinson's, the accumulation of misfolded protein intermediates leads to proteotoxic stress and cellular dysfunction (Balch et al., 2008, Science). Therapeutic interventions targeting these states include the use of chemical chaperones to stabilize folding, heat shock protein modulators to enhance the cellular folding capacity, and small molecules that bind nascent chains to influence translation (Kramer et al., 2009, Nature). Because these proteins are central to all cellular functions, targeting them requires high specificity to avoid disrupting global proteostasis (Hipp et al., 2014, Nature Reviews Molecular Cell Biology). Furthermore, the ribosome-associated quality control (RQC) system and the ubiquitin-proteasome system work in tandem to degrade nascent chains that fail to fold correctly, making these pathways attractive targets for drug development in cancer and protein-misfolding disorders.

Other names

Nascent polypeptide chainsUnfolded proteinsMisfolded protein intermediatesCo-translational folding intermediatesRibosome-bound nascent chains

Modulation of molecular chaperones, kinetic stabilization of folding intermediates, and pharmacological chaperoning to prevent aggregation or promote degradation.