In This Issue

124 A galaxy of folds

Vikram Alva, Michael Remmert, Andreas Biegert, Andrei N. Lupas, and Johannes Söding

Despite their enormous sequence diversity, proteins are built of recurrent domains belonging to only a few thousand fold types. Did these folds originate independently multiple times, converging on similar structural solutions, or did they evolve divergently from ancestral prototypes? In this study, Söding and co-workers clustered domains of known structure by their sequence similarity, a property that reflects common descent. They report that, while some highly populated folds indeed appear to have evolved convergently, most domains possessing the same fold arose from an ancestral prototype. They also report that occasionally, domains belonging to different folds cluster together, connected by recurrent fragments which may be descendants of an ancestral pool of peptide modules from which the first folded proteins arose.

94 The hydrodynamic and conformational properties of denatured proteins in dilute solutions

Guy C. Berry

Estimates of the root-mean-square radius of gyration RG of denatured proteins versus the number N of residues based on the intrinsic viscosity versus N using expressions appropriate for linear flexible-chain polymers give estimates of RG/□N consistent with the rotational-isomeric state RIS model. Recent direct measurements of RG give smaller values of RG/□N than deduced from those estimates, or RG/□N computed using a model with conformational constraints. It is suggested that consistent with NMR observations, transient loops created by intrachain association in the denatured state, resulting in an effective nonlinearity of the denatured chain in dilute solution can reconcile these apparently disparate observations.

34 Thermodynamic and structural insights into CSL-DNA complexes

David R. Friedmann and Rhett A. Kovall

The Notch pathway is a highly conserved signaling mechanism, in which extracellular signals are ultimately transduced into changes in gene expression via the DNA binding protein CSL. Despite being identified over twenty years ago, very little is understood at the quantitative level regarding the affinity of CSL for DNA. Here Friedmann and Kovall report a comprehensive thermodynamic and structural analysis of CSL binding to the two DNA sites that comprise the HES-1 response element - a known Notch target gene. Previously, it was thought that CSL binds DNA with high affinity; however, our findings demonstrate that CSL only has moderate affinity for DNA, which suggests that DNA binding by CSL is likely a more regulated process than previously appreciated.

141 Sequence periodicity and secondary structure propensity in model proteins

Giovanni Bellesia, Andrew Iain Jewett, and Joan-Emma Shea

In this report, Bellesia, et al. use a simplified computational model to study the relative importance of local effects - those originating from the amino acids intrinsic secondary structure propensitie - and non-local effects - those reflecting the sequence of amino acids as a whole - in determining a protein's fold. Their simulations show that the fold of small, globular proteins is mainly determined by the pattern of polar and non-polar amino acids regardless of their intrinsic secondary structure propensities. These results quantitatively agree with, and extend, previous experimental observations.