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Controlling protein function by fine-tuning conformational flexibility.

ABSTRACT: In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions typically affect larger (sub-)domains, and global changes affect the whole protein non-specifically. Herein, we directly observe protein regulation under three different degrees of localization, and present the effects on the Hsp90 chaperone system at the levels of conformational steady states, kinetics and protein function. Interestingly using single-molecule FRET, we find that similar functional and conformational steady states are caused by completely different underlying kinetics. We disentangle specific and non-specific effects that control Hsp90's ATPase function, which has remained a puzzle up to now. Lastly, we introduce a new mechanistic concept: functional stimulation through conformational confinement. Our results demonstrate how cellular protein regulation works by fine-tuning the conformational state space of proteins.

SUBMITTER: Schmid S

PROVIDER: S-EPMC7375816 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Controlling protein function by fine-tuning conformational flexibility.

Schmid Sonja S Hugel Thorsten T

eLife 20200722

In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions typically affect larger (sub-)domains, and global changes affect the whole protein non-specifically. Herein, we directly observe protein regulation under three different degrees of localization, and pr ...[more]

PMID: 32697684

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Project description:RATIONALE:PGC1? (peroxisome proliferator-activated receptor gamma coactivator 1?) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1? expression as a therapy, for instance, causing cardiomyopathy. OBJECTIVE:To determine whether a fine-tuning of PGC1? expression is essential for cardiac homeostasis in a context-dependent manner. METHODS AND RESULTS:Moderate cardiac-specific PGC1? overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc-/- (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1? expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1? expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1? (PGC1?OE) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1? knock in in G3 (G3 PGC1?OE) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1?OE mice. In the context of telomere dysfunction, PGC1? induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart. CONCLUSIONS:Fine-tuning the expression of PGC1? is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1?-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.

Dataset Information

Controlling protein function by fine-tuning conformational flexibility.

Publications

Controlling protein function by fine-tuning conformational flexibility.

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