Non-native, aggregation-prone client proteins

Non-native, aggregation-prone client proteins are polypeptides that have lost their functional three-dimensional fold and are susceptible to forming toxic intracellular or extracellular aggregates (Balch et al., 2008 [1]). These proteins are the primary substrates of the cellular proteostasis network, which employs molecular chaperones like Hsp70 and Hsp90 to facilitate refolding or to target terminally misfolded species for degradation via the ubiquitin-proteasome system or autophagy (Hipp et al., 2014 [2]). In neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, the failure to clear these aggregation-prone species leads to proteotoxicity and the formation of characteristic pathological inclusions like amyloid plaques and Lewy bodies (Chiti & Dobson, 2006 [3]). Conversely, in many cancers, oncogenic proteins (e.g., mutated p53 or BCR-ABL) exist in a non-native state that requires constant stabilization by chaperones to maintain activity and avoid degradation (Taipale et al., 2010 [4]). Therapeutic strategies targeting this class include Hsp90 inhibitors that trigger the degradation of oncogenic clients, and chemical chaperones like 4-phenylbutyrate that stabilize protein folds to prevent aggregation (Neckers & Workman, 2012 [5]; Cortez & Sim, 2014 [6]). Monitoring the efficacy of such treatments often involves measuring the depletion of specific client proteins or the compensatory induction of heat shock proteins like Hsp70 (Powers et al., 2009 [7]). Sources: [1] Science 319(5865):916-9; [2] Nat Rev Mol Cell Biol 15(12):762-74; [3] Annu Rev Biochem 75:333-66; [4] Nat Rev Mol Cell Biol 11(7):515-28; [5] Clin Cancer Res 18(1):64-76; [6] Prion 8(2):197-202; [7] Annu Rev Biochem 78:959-91.

Other names

Misfolded proteinsUnfolded proteinsChaperone client proteinsProteotoxic speciesAggregation-prone proteins

Modulation of the cellular proteostasis network through the inhibition of molecular chaperones to promote client degradation, the induction of heat shock proteins to enhance folding capacity, or the use of chemical and pharmacological chaperones to stabilize native protein conformations.