Chaperone-Like Activity of Human Small Heat Shock Protein-Derived Peptides in Response to Cellular Stress
Date
2019-06-18
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Abstract
Small heat shock proteins (sHsps), a family of molecular chaperones that prevent
aggregation of partially unfolded protein substrates, are present in many different
organisms across all domains of life. They work to maintain cellular function and
survival under stress conditions, such as high temperatures, by binding
non-natively folded proteins in an ATP-independent manner. This is followed by
either promotion of proper protein folding or facilitation of protein degradation.
Malfunction of sHsps in humans has been implicated in the development of
several morbidities, particularly in neurological diseases where accumulation of
misfolded proteins leads to neurodegeneration. sHsps contain an “alpha-crystallin
domain” (ACD) flanked by an N- and C-terminal region (NTR and CTR,
respectively) of varying length and sequence. These terminal regions are believed
to participate in substrate and quaternary interactions. Their quaternary
interactions result in the formation of dynamic oligomers whose physiological
relevance and role in chaperone activity has yet to be determined.
This work includes two projects, both with aims to identify functional regions of
sHsps that contain chaperone activity. In the first, purifying the relatively
unstructured N-terminal sequence from human HspB1 and analyzing its
interaction with model substrates, we have identified an 88-residue sequence that
exhibits chaperone activity in solution. We constructed gold nanoparticles
(AuNPs) conjugated to the HspB1 NTR to explore the importance of the
oligomeric interactions of the molecular chaperone in binding to its substrate.
These sHsp-AuNPs were found to exhibit chaperone activity, with the chaperone
capacity varying by substrate and AuNP diameter. Our combined results indicate
the particular importance of the NTR in sHsp chaperone activity and demonstrate
the therapeutic potential of sHsp-AuNPs.
The second project evaluated the chaperone-like activity of mini alpha-Crystallin
A (CryAAID1), residues 70-88 of human sHsp alpha-Crystallin A. This peptide
was also conjugated to AuNPs and results confirmed CryAAID1 maintained
chaperone activity in the absence of other sHsp domains. Substrate specificity
AuNP diameter dependence were also demonstrated.
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Keywords
Small heat shock proteins, sHsps, nanoparticles, aggregation