Order from Disorder: Defining 'Structure' in Disordered Proteins
Elizabeth Rhoades, Yale University

Many diverse and critical cellular functions, ranging from muscle contraction to immune protection to transport and storage of small molecules, are dependent upon proteins. Proteins are synthesized as linear chains of amino acids which ‘fold’ into compact three dimensional globular states consisting of secondary structures – α-helices and -sheets – as well as specific tertiary contacts. The process by which proteins undergo this conformational transition is termed the ‘protein folding problem’ and it has been studied for decades by a wide variety of biophysical, biochemical, theoretical, and computational approaches. Part of the motivation for such intensive study is the underlying assumption that the function of a protein is critically dependent upon its ability to fold correctly. This assumption is certainly true for the majority of proteins and a number of devastating diseases are linked to incorrect protein folding. However, there is a growing recognition that a large fraction – by some estimates as many as 40% in eukaryotes – do not fit this mold. These proteins are called intrinsically disordered or natively unfolded and, as their name implies, they do not form stable secondary or tertiary structures under physiological conditions. For many, their function is dependent upon their ability to remain unfolded or to only fold when binding to a specific molecular target. Disordered proteins are conformationally flexible, highly dynamic, and promiscuous binders. These properties present a striking contrast to the structure-function paradigm that dominates our understanding of proteins and presents a challenge for characterizing their functional, and in many cases, dysfunctional interactions. We are motivated to understand how to define a ‘structure-function’ relationship in the context of the dynamic conformational ensembles populated by disordered proteins.

Background Review Article:
Dunker, A. Keith, and Richard W. Kriwacki. "The orderly chaos of proteins." Scientific American 304.4 (2011): 68-73.

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