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Protein aggregation can occur due to a variety of causes. Individuals
may have mutations that encode for proteins that are particularly
sensitive to misfolding and aggregation. Alternatively, disruption of
the pathways to refold proteins (chaperones) or to degrade misfolded
proteins (the ubiquitin-proteasome pathway) may lead to protein
aggregation. As many of the diseases associated with protein aggregation
increase in frequency with age, it seems that cells lose the ability to
clear misfolded proteins and aggregates over time. Several new studies
suggests that protein aggregation is a second line of the cellular
reaction to an imbalanced protein homeostasis rather than a harmful,
random process.[7]. A groundbreaking study[8]
showed that sequestration of misfolded, aggregation-prone proteins into
inclusion sites is an active organized cellular process, that depends
on quality control components, such as HSPs and co-chaperones. Moreover,
it was shown that eukaryotic cells have the ability to sort misfolded proteins in to two quality control compartments: 1. The JUNQ (JUxta Nuclear Quality control compartment). 2. The IPOD
(Insoluble Protein Deposit). The partition into two quality control
compartments is due to the different handling and processing of the
different kinds of misfolded aggregative proteins: The IPOD serves as a
sequestration site for non-ubiquitinated terminally aggregated proteins,
such as the huntingtin protein. Under stress conditions, such as heat,
when the cellular quality control machinery is saturated, ubiquitinated
proteins are sorted to the JUNQ compartment, where they are eventually
degraded. Thus, aggregation is a regulated, controlled process.
Exposed hydrophobicity is a key determinant of nuclear quality control degradation
Protein quality control (PQC) degradation protects the cell by
preventing the toxic accumulation of misfolded proteins. In
eukaryotes, PQC degradation is primarily achieved
by ubiquitin ligases that attach ubiquitin to misfolded proteins for
proteasome
degradation. To function effectively, PQC ubiquitin
ligases must distinguish misfolded proteins from their normal
counterparts
by recognizing an attribute of structural
abnormality commonly shared among misfolded proteins. However, the
nature of the
structurally abnormal feature recognized by most
PQC ubiquitin ligases is unknown. Here we demonstrate that the yeast
nuclear
PQC ubiquitin ligase San1 recognizes exposed
hydrophobicity in its substrates. San1 recognition is triggered by
exposure of
as few as five contiguous hydrophobic residues,
which defines the minimum window of hydrophobicity required for San1
targeting.
We also find that the exposed hydrophobicity
recognized by San1 can cause aggregation and cellular toxicity,
underscoring
the fundamental protective role for San1-mediated
PQC degradation of misfolded nuclear proteins.
Amyloidogenic Regions and Interaction Surfaces Overlap in Globular Proteins Related to Conformational Diseases
Protein aggregation underlies a wide range of human disorders. The
polypeptides involved in these pathologies might be intrinsically
unstructured or display a defined 3D-structure. Little is known about
how globular proteins aggregate into toxic assemblies under
physiological conditions, where they display an initially folded
conformation. Protein aggregation is, however, always initiated by the
establishment of anomalous protein-protein interactions. Therefore, in
the present work, we have explored the extent to which protein
interaction surfaces and aggregation-prone regions overlap in globular
proteins associated with conformational diseases. Computational analysis
of the native complexes formed by these proteins shows that
aggregation-prone regions do frequently overlap with protein interfaces.
The spatial coincidence of interaction sites and aggregating regions
suggests that the formation of functional complexes and the aggregation
of their individual subunits might compete in the cell. Accordingly,
single mutations affecting complex interface or stability usually result
in the formation of toxic aggregates. It is suggested that the
stabilization of existing interfaces in multimeric proteins or the
formation of new complexes in monomeric polypeptides might become
effective strategies to prevent disease-linked aggregation of globular
proteins.
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