How cells ensure the integrity of their proteome, and maintain protein homeostasis,
has emerged as one of the most fascinating and medically relevant areas of molecular cell biology.
This exciting development is the result of a paradigm shift in our understanding of how proteins fold in the cell,
which has occurred over the last two decades.
We no longer believe that newly-synthesized polypeptides fold in
a spontaneous process, solely dependent on
the steric information contained in the amino acid sequences.
Instead, it is clear that many proteins require assistance from molecular chaperones,
to realize their inbuilt potential to fold efficiently, and at a biologically relevant timescale.
This machinery is not only required for folding under normal conditions,
but also under various conditions of stress.
Moreover, chaperones are also linked with
important diseases in which proteins mis-fold and aggregate,
including some of the most debilitating neurodegenerative diseases.
The discovery of a particular class of molecular chaperones,
the so-called 'chaperonins', was critical in the development of these insights.
Protein folding is the final step in the information transfer from gene to functional protein,
and as such, it is arguably one of the most important processes in biology.
Folding is a complex search process, in which the linear information in
the amino acid sequence gives rise to
the defined and unique 3-dimensional conformation of a protein's native state.
In effect, folding is a polymer condensation process, in which
an astronomically large number of possible unfolded conformers
(shown here for the small protein Barnase) converge
rapidly through multiple pathways, to a set of so-called 'random globules'.
These are relatively compact conformations containing
secondary structure elements, but lacking defined tertiary interactions.
Further restriction in configurational entropy, through
the formation of native context, finally leads
this ensemble to the single defined structure of
the native state, in which hydrophobic amino acid residues are buried within a tightly-folded hydrophobic core.
There has been significant progress in recent years in
understanding the structural basis of protein folding,
but we're still unable to predict the three-dimensional structure of a protein just from its sequence.
How do cells solve the protein folding problem?