Available online at www.sciencedirect.com
Take home lessons from studies of related proteins
*
Adrian A Nickson, Beth G Wensley and Jane Clarke
The ‘Fold Approach’ involves a detailed analysis of the folding The malleability of protein folding pathways
of several topologically, structurally and/or evolutionarily A unifying folding mechanism
related proteins. Such studies can reveal determinants of the In the early days of the ‘protein-folding problem’, three
folding mechanism beyond the gross topology, and can dissect competing mechanisms were proposed that described
the residues required for folding from those required for stability how a polypeptide chain might fold to the native state:
or function. While this approach has not yet matured to the nucleation [3], hydrophobic-collapse [4] and diffusion-
point where we can predict the native conformation of any collision (framework) [5]. However, an early F-value
polypeptide chain in silico, it has been able to highlight, analysis of the small protein chymotrypsin inhibitor 2
amongst others, the specific residues that are responsible for (CI2) demonstrated that none of these mechanisms was
nucleation, pathway malleability, kinetic intermediates, chain appropriate, since secondary and tertiary structure formed
knotting, internal friction and Paracelsus switches. Some of the concomitantly [6]. Thus the nucleation-condensation
most interesting discoveries have resulted from the attempt to mechanism was introduced [7], in which long-range con-
explain differences between homologues. tacts set up the initial topology of the protein (incurring a
Address substantial entropic loss with minimal enthalpic gain),
Department of Chemistry, University of Cambridge, Lensfield Rd, followed by a rapid collapse to the native state (with
Cambridge CB2 1EW, UK minimal entropic loss but substantial enthalpic gain).
Under these conditions, the transition state is usually
Corresponding author: Nickson, Adrian A ([email protected])
an expanded form of the native state [8], which helps
* to explain the strong correlation between native topolo-
Current address: MedImmune, Granta Park, Cambridge CB21 6GH,
UK. gical complexity (Contact Order) and folding rates, as
noted by Plaxco and Baker in the late 1990s [9].
Current Opinion in Structural Biology 2013, 23:66–74
Although the nucleation-condensation mechanism is
This review comes from a themed issue on Folding and binding
observed to be widely applicable, several proteins have
Edited by Jayant Udgaonkar and Susan Marqusee been shown to fold in a more hierarchical manner. In
For a complete overview see the Issue and the Editorial particular, the engrailed homeodomain (En-HD) was
seen to fold via a classical framework mechanism [10].
Available online 20th December 2012
To investigate whether this result was owing to the
0959-440X/$ – see front matter, # 2012 Elsevier Ltd. All rights
simple architecture of the protein, Fersht and co-workers
reserved.
studied four other members of the homeodomain-like
http://dx.doi.org/10.1016/j.sbi.2012.11.009
superfamily: c-Myb, hRAP1, Pit1 and hTRF1. They
observed a slide in mechanism a slide from hTRF1 (pure
nucleation-condensation) to En-HD (pure framework)
Introduction through c-Myb, hRAP1 and Pit1 (mixed mechanisms),
In the fifty years since the protein-folding field was first which correlated with the innate secondary structural