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Proteomic characterization of Hsp78-interacting proteins highlights chaperone role during protein aggregation in mitochondria under heat stress - Part A Protein Interactions

ABSTRACT: Chaperones of the Hsp100 chaperone family support protein homeostasis, the maintenance of protein activity under stress, by refolding aggregated proteins or targeting them for degradation. Hsp78, the ClpB-type mitochondrial member of the Hsp100 family, can be found in lower eukaryotes like yeast. Although Hsp78 has been shown to contribute to protection against elevated temperatures in yeast, the biochemical mechanisms underlying this mitochondria-specific thermotolerance are still largely unclear. To identify endogenous chaperone substrate proteins, we generated an Hsp78-ATPase mutant with a stabilized substrate binding behavior. We used two SILAC-based quantitative mass spectrometry approaches to analyze the role of Hsp78 during heat stress-induced mitochondrial protein aggregation and disaggregation processes on a proteomic level. In the first setup, Hsp78-interacting polypeptides were identified to reveal the endogenous substrate spectrum of the chaperone. Our analysis revealed that Hsp78 is interacting with a wide variety of proteins related to metabolic functions including energy production and protein synthesis, as well as other chaperones, thus maintaining crucial functions for mitochondrial stress resistance. We compared these interaction data with a second experimental setup that focused on the on overall aggregation and disaggregation processes in mitochondria under heat stress on a proteomic level. This revealed specific aggregation-prone protein populations and demonstrated the direct quantitative impact of Hsp78 on stress-dependent protein solubility different conditions and. We conclude that Hsp78 together with its cofactors represents a recovery system that protects major mitochondrial metabolic functions during as well restores protein biogenesis capacity after heat stress.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Marc Sylvester

LAB HEAD: Wolfgang Voos

PROVIDER: PXD030405 | Pride | 2022-09-20

REPOSITORIES: Pride

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Project description:Proctor2005 - Actions of chaperones and their role in ageing This model is described in the article: Modelling the actions of chaperones and their role in ageing. Proctor CJ, Soti C, Boys RJ, Gillespie CS, Shanley DP, Wilkinson DJ, Kirkwood TB. Mech. Ageing Dev. 2005 Jan; 126(1): 119-131 Abstract: Many molecular chaperones are also known as heat shock proteins because they are synthesised in increased amounts after brief exposure of cells to elevated temperatures. They have many cellular functions and are involved in the folding of nascent proteins, the re-folding of denatured proteins, the prevention of protein aggregation, and assisting the targeting of proteins for degradation by the proteasome and lysosomes. They also have a role in apoptosis and are involved in modulating signals for immune and inflammatory responses. Stress-induced transcription of heat shock proteins requires the activation of heat shock factor (HSF). Under normal conditions, HSF is bound to heat shock proteins resulting in feedback repression. During stress, cellular proteins undergo denaturation and sequester heat shock proteins bound to HSF, which is then able to become transcriptionally active. The induction of heat shock proteins is impaired with age and there is also a decline in chaperone function. Aberrant/damaged proteins accumulate with age and are implicated in several important age-related conditions (e.g. Alzheimer's disease, Parkinson's disease, and cataract). Therefore, the balance between damaged proteins and available free chaperones may be greatly disturbed during ageing. We have developed a mathematical model to describe the heat shock system. The aim of the model is two-fold: to explore the heat shock system and its implications in ageing; and to demonstrate how to build a model of a biological system using our simulation system (biology of ageing e-science integration and simulation (BASIS)). This model is hosted on BioModels Database and identified by: BIOMD0000000091. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Proteomic characterization of Hsp78-interacting proteins highlights chaperone role during protein aggregation in mitochondria under heat stress - Part A Protein Interactions

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