Molecular medicine-Introduction

Protein misfolding and aggregation have
been recognized for many years as common
processes. Aggregation can occur
under various conditions. The aggregation
of which we are speaking is very different
from the precipitation of a native protein
at the isoelectric point or upon salting
out, which can be reversed under appropriate
conditions. In the precipitate, the
protein remains in a native conformation.
The aggregates, however, are formed from
partially folded intermediates and result
from intermolecular interactions, which
compete with intramolecular interactions.
Thermal denaturation of proteins is frequently
accompanied by the formation
of aggregates leading to the irreversibility
of the process. As early as 1931,
Wu, in a review on protein denaturation,
distinguished between aggregation and
precipitation. The aggregated species are
not in equilibrium with the soluble species,
complicating experimental approaches.
Aggregation has been reported to occur
during the in vitro refolding ofmonomeric
as well as oligomeric proteins, lowering
the refolding yield. As mentioned above,
the use of very low protein concentrations
could prevent protein aggregation.
However, during the folding of nascent
polypeptide chains biosynthesized within
prokaryotic and eukaryotic cells, aggregates
can accumulate. The overexpression
of genes in foreign hosts often result
in aggregated nonnative proteins called
inclusion bodies, which are disordered aggregates,
leading to serious limitation in
the production of recombinant proteins.
It is a real problem needing a lot of
effort to fully exploit the sequence information
contained in the genome projects.
Ordered aggregates resulting in amyloid
fibrils lead to a number of serious human
diseases such as Alzheimer’s disease
and the transmissible spongiform encephalopathies.
The formation of amyloid
aggregates has also been reported in in
vitro experiments.
Experimental and theoretical studies
together have provided significant insights
into the mechanisms of protein folding,
also allowing a better understanding of the
aggregation processes.
The following different aspects of protein
aggregation must be considered:
1. Theoretical and methodological aspects
of protein folding, misfolding, and
aggregation including the detection of
aggregates and the mechanisms of
aggregation processes.
2. Protein aggregation in the cellular environment
including the folding into
the cell, the role of molecular chaperones,
and the formation of different
aggregate morphologies, as well as the
pathological consequences