Accessing the Unfolded part of the Proteome from NMR : A Step Forward in Structural Biology

The central dogma that has motivated massive worldwide investment in structural genomic projects has been founded upon the assumption that the resolution of the three dimensional structure of a finite number of proteins will provide the key to understanding biological activity.

However, over the last decade it has become increasingly clear that a large fraction (up to 40%) of the proteins encoded by the human genome are intrinsically disordered or contain disordered regions of significant length. These intrinsically disordered proteins (IDPs) are functional despite a lack of a stable structure. The classical structure-function paradigm therefore breaks down for this class of proteins, and new insight into the relationship between primary sequence and molecular function is required.

The importance of developing new methodology to study these proteins is underlined by the fact that IDPs are associated with many human diseases, including cancer, cardiovascular disease, amyloidosis, neurodegenerative disease and diabetes. Vital molecular processes, their function, malfunction and potential inhibition by pharmaceutical agents, have escaped our attention for decades, and will continue to do so, unless we can develop the tools to study these elusive proteins.

The development of meaningful descriptions of the conformational behavior of IDPs therefore represents a key challenge for contemporary structural biology. Recent advances at the Institut de Biologie Structurale (CEA-CNRS-UJF) in Grenoble using Nuclear Magnetic Resonance spectroscopy demonstrate that atomic resolution understanding of the behaviour of these proteins can be derived from the simplest NMR measurements, chemical shifts. Chemical shifts are uniquely dependent on local conformational sampling, and in this study it is shown that explicit consideration of the dynamic averaging of chemical shifts provides an accurate description of the ensemble of conformers present in solution.

This breakthrough raises a long-standing, and fundamental barrier to our understanding of these intriguing proteins, and offers the very real prospect of following the conformational behavior of IDPs under conditions approaching those found in vivo, such as in crowded or even cellular environments.

Defining Conformational Ensembles of Intrinsically Disordered and Partially Folded Proteins Directly from Chemical Shifts. M.R. Jensen, L. Salmon, G. Nodet and M. Blackledge. Journal of the American Chemical Society, online, 2010.