Intrinsically Disordered Proteins and Their Functions

A fundamental tenet of structural and molecular biology is that the function of a protein is closely linked to its three-dimensional structure; conversely, it is assumed that knowledge of the structure of a protein can provide insights into its biological function. However, a significant proportion of gene sequences appear to code not for folded globular proteins but for proteins that are intrinsically disordered. Analysis of genome sequences reveals that a very high proportion of proteins are intrinsically disordered, especially in higher eukaryotes. Such proteins perform key regulatory functions in the cell, often undergoing folding transitions upon binding to their cellular targets. These functions include regulation of transcription, translation, and the cell cycle, and control of complex signal transduction networks. The lack of stable globular structure confers many functional advantages, but not without cost; many disordered proteins are associated with neurodegenerative diseases and with chromosomal translocations in cancer. Intrinsically disordered proteins as a class occupy a continuum of “conformational space”, ranging from highly unstructured, through molten globule, to local disorder within an otherwise folded domain. The functional interactions of intrinsically disordered proteins are commonly modulated by post translational modifications, leading to biological switches and rheostats. The inherent properties of disordered proteins make them ideally suited for control of dynamic cellular regulatory networks. In keeping with their critical regulatory functions, the cellular abundance of intrinsically disordered proteins is tightly controlled. Many viruses hijack their host cells by make extremely effective use of intrinsic disorder to mimic key cellular regulatory proteins that are themselves intrinsically disordered.