Introduction

It has been known from long that the folding of proteins to their native state is a
complicated pathway, which may often lead to misfolded structures with compromised
functionality. The mistake in folding is often a result of molecular crowding (due to large size
of protein or high concentration in overexpressed conditions), or changes in system
conditions, where both of these can be found as culprit for disturbing the route of attaining
final conformation. Aside from in-vitro folding when it comes to actual folding of proteins in
cells, the event becomes even more complicated and may often result into highly inefficient
folding.
Misfolded proteins are the polypeptide conformations stuck in local minimas with inability
to regain their functional states spontaneously. Such misfolded proteins in general are
found to have hydrophobic regions exposed and hence prone to aggregation due to
hydrophobic interactions. As the proper folding of proteins in eukaryotic system is
associated with number of functions (e.g. trafficking of various molecules to organelles, cell
cycle and immune response), the inefficient folding to native state can be detrimental for
cellular health and can cause numerous disorders.
Considering the seriousness of the issue, the biology of cells has evolved itself to provide
solution through a mechanism that inhibits the aggregation, as well as provides correct path
for folding of nascent polypeptides. Central to such mechanisms are class of molecules,
known as Chaperones. Based on their chemical nature and functions chaperones can be
classified as (i) Chemical (small chemical species inhibits aggregation) (ii) Molecular (large
protein molecules, inhibits aggregation and shows foldase activity) or (iii) Pharmacological
(chemical species acting as weak ligand or inhibitors) in nature.
It has been found that despite the presence of several mechanisms for controlling
misfolding and aggregation in cells, the protein homeostasis can sometimes go haywire due
to several reasons (e.g. genetic or metabolic) resulting into uncontrolled protein stress and
malfunctionality. The misfolded and aggregated proteins interact with other cellular
components causing cell death and reduced cell viability.
or can form intrinsic toxic species (e.g. amyloids) which can result into number of
degenerative disorders. The harmful effects of protein misfolding and aggregation can also
be attributed to their tendency to signal variety of pathways or interfere with the already
existing ones, causing number of diseases.