Cellular Stress and Protein Misfolding During Aging - Protein Misfolding and Cellular Stress in Disease and Aging - page 107

responsible for building up surface adhesive organelles whereby
the chaperones supply steric information to their substrate pro-
teins ( 22 ). An example of this is seen in the pilus subunits of
gram-negative bacteria where PapD-like chaperones (of which
more than 30 members exist in this superfamily) actually donate
a beta strand of their own to the subunit to stabilise the complex
( 23 ). Interestingly, in the absence of the chaperone, a protease
DegP, which recognises misfolded, denatured, and/or aggre-
gated proteins, takes over, and degrades the now unstable sub-
units. DegP in itself has recently been shown not to be just a
protease but more of a protease-chaperone. It has been observed
that the binding of misfolded proteins transforms hexameric
DegP into large active 12- or 24-mers where the highly flexible
inner cavity serves opposite functions depending on the substrate
( 24 ), where outer membrane proteins are provided a safe transit
while misfolded proteins are degraded within the same interior.

3. Stress and
Protein Misfolding

Cells are under constant onslaught from several intrinsic and
extrinsic stressors, which range from physical and metabolic stres-
sors to environmental and genetic stressors. These also include
changes in the microenvironment of the cell, up- or down-regu-
lation of concentrations of metabolites and/or osmolytes (that
can induce protein stability changes), temperature changes, pH
changes, and so on. The consequent protein misfolding, if not
rescued in time, can result in aberrant aggregate formation, whose
accumulation can eventually lead to the onset of a disease pheno-
type. How cellular stress and protein misfolding overwhelm the
protein quality control mechanisms to cause disease in the con-
text of aging is discussed below.

3.1. Protein
Homeodynamics
in a Cell

“Proteostasis” has been suggested as a term to describe the con-
trol of the protein concentration, conformation, binding interac-
tions, and cellular location by readapting the internal biology of
the cell mostly through transcriptional and translational changes
( 25 ). Since the above processes are generally very dynamic, it may
be more appropriate to call it as “proteodynamics,” in line with
increasing replacement of the term “homeostasis” with “homeo-
dynamics” in biological systems ( 26 ). Indeed the protein quality
control mechanisms within a cell, utilising various assistants in the
protein folding pathway and other competing degradation path-
ways, indicate that proteodynamics plays a critical role in the cell.
Evidence for the importance of the quality control is also high-
lighted by the fact that up to half of all the polypeptide chains fail to
satisfy the quality control mechanism in the endoplasmic reticulum