The aggregation of misfolded proteins is associated with the perturbation of cellular function, ageing and various human disorders. Mounting evidence suggests that protein aggregation is often part of the cellular response to an imbalanced protein homeostasis rather than an unspecific and uncontrolled dead-end pathway. It is a regulated process in cells from bacteria to humans, leading to the deposition of aggregates at specific sites. The sequestration of misfolded proteins in such a way is protective for cell function as it allows for their efficient solubilization and refolding or degradation by components of the protein quality-control network. The organized aggregation of misfolded proteins might also allow their asymmetric distribution to daughter cells during cell division.

/pdf/cellular-strategies-for-controlling-protein-aggregation-56fg1zgq9j.pdf

Cellular strategies for controlling protein aggregation

Interpretation of mass spectra is challenging because they report a ratio of two physical quantities, mass and charge, which may each have multiple components that overlap in m/z. Previous approaches to disentangling the two have focused on peak assignment or fitting. However, the former struggle with complex spectra, and the latter are generally computationally intensive and may require substantial manual intervention. We propose a new data analysis approach that employs a Bayesian framework to separate the mass and charge dimensions. On the basis of this approach, we developed UniDec (Universal Deconvolution), software that provides a rapid, robust, and flexible deconvolution of mass spectra and ion mobility-mass spectra with minimal user intervention. Incorporation of the charge-state distribution in the Bayesian prior probabilities provides separation of the m/z spectrum into its physical mass and charge components. We have evaluated our approach using systems of increasing complexity, enabling us to ...

/pdf/bayesian-deconvolution-of-mass-and-ion-mobility-spectra-from-grk678rg1p.pdf

Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles.

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(11)00190-3.pdf

Small heat shock proteins and α-crystallins: dynamic proteins with flexible functions.

https://www.dbt.univr.it/documenti/OccorrenzaIns/matdid/matdid710774.pdf

A first line of stress defense: small heat shock proteins and their function in protein homeostasis.

Small heat shock proteins: Role in cellular functions and pathology.

Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that prevent protein aggregation by binding clients destabilized during cellular stress. Here we probe the architecture and dynamics of complexes formed between an oligomeric sHSP and client by employing unique mass spectrometry strategies. We observe over 300 different stoichiometries of interaction, demonstrating that an ensemble of structures underlies the protection these chaperones confer to unfolding clients. This astonishing heterogeneity not only makes the system quite distinct in behavior to ATP-dependent chaperones, but also renders it intractable by conventional structural biology approaches. We find that thermally regulated quaternary dynamics of the sHSP establish and maintain the plasticity of the system. This extends the paradigm that intrinsic dynamics are crucial to protein function to include equilibrium fluctuations in quaternary structure, and suggests they are integral to the sHSPs' role in the cellular protein homeostasis network.

/pdf/quaternary-dynamics-and-plasticity-underlie-small-heat-shock-1s86swug8i.pdf

Alexander J. Painter

Papers

Quaternary dynamics and plasticity underlie small heat shock protein chaperone function

Real-Time Monitoring of Protein Complexes Reveals their Quaternary Organization and Dynamics