Intrinsically Disordered Proteins

The traditional structure-function paradigm equates protein function with a well-defined three-dimensional structure. This view is based on tens of thousands of high-resolution structures in the Protein Data Bank, which provide the foundation for our understanding of protein function and malfunction. Rapid progress in the classical field of structural biology over the past decades, however, has led to many observations that apparently did not to fit into this unifying scheme. There has been a steady increase in the number of proteins/protein domains that resembled highly denatured proteins, although they were studied under native conditions. By the end of the 1990s, the exceptions that violated the rule had become so extensive that their existence could no longer be ignored. This increase called for a re-assessment of the structure-function paradigm. The feverish activity that followed has brought disordered proteins into the spotlight, and transformed our basic views of protein structure and function. It has been realized that structurally disordered proteins provide many functional advantages and enable functions completely out of the reach of globular proteins. Protein disorder was found to prevail in regulatory and signaling functions, and its frequency increased sharply in evolution from prokaryotes to eukaryotes. The structure-function characterization of these proteins now poses a major challenge to proteomic and small-scale studies alike, and has already reached epic proportions. In this review the history, recent focus and possible future directions of IDP research are surveyed.