Seminar

Intrinsically Disordered Proteins and their study by NMR spectroscopy

FRANS MULDER

The traditional structure-function paradigm drastically needs revision due to the discovery that the genomes of higher organisms encode substantial fractions (> 30%) of largely or fully intrinsically disordered proteins (IDPs) or domains, and the fact that these are involved in central cellular functions, such as transcription regulation and cell signaling. In addition, disordered polypeptides are potentially toxic to the cell, and IDPs are implicated in a number of widespread human pathologies, such as Parkinson's and Alzheimer's disease. NMR spectroscopy is singular in its capacity to study intrinsically disordered proteins (IDPs) with atomic detail. Due to the lack of a unique three-dimensional structure, IDPs are not amenable to X-ray crystallography, but the conformational state of IDPs can be described by extensive ensembles, derived from NMR and complementary experimental data. I will present an alternative to comprehensive structure determination, which is based on the use of NMR chemical shifts. With this method, we can faithfully detect the relative tendency of the polypeptide chain to adopt either helical or extended conformations at any point in the primary sequence, with atomic resolution. This offers a new and sensitive proxy for changes in protein (dis)order and dynamics, which may either be functional, or lethal to the cell.