A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins.

HSP27 is a human molecular chaperone that forms large, dynamic oligomers and functions in many aspects of cellular homeostasis. Mutations in HSP27 cause Charcot-Marie-Tooth (CMT) disease, the most common inherited disorder of the peripheral nervous system. A particularly severe form of CMT disease is triggered by the P182L mutation in the highly conserved IxI/V motif of the disordered C-terminal region, which interacts weakly with the structured core domain of HSP27.

Weighing-up protein dynamics: the combination of native mass spectrometry and molecular dynamics simulations.

Structural dynamics underpin biological function at the molecular level, yet many biophysical and structural biology approaches give only a static or averaged view of proteins. Native mass spectrometry yields spectra of the many states and interactions in the structural ensemble, but its spatial resolution is limited. Conversely, molecular dynamics simulations are innately high-resolution, but have a limited capacity for exploring all structural possibilities.

Mass spectrometry beyond the native state.

Native mass spectrometry allows the study of proteins by probing in vacuum the interactions they form in solution. It is a uniquely useful approach for structural biology and biophysics due to the high resolution of separation it affords, allowing the concomitant interrogation of multiple protein components with high mass accuracy. At its most basic, native mass spectrometry reports the mass of intact proteins and the assemblies they form in solution.