Protein susceptibility to oxidation and cell phenotype alterations

Lovrić, Anita (2016) Protein susceptibility to oxidation and cell phenotype alterations. Doctoral thesis, Faculty of Science > Department of Biology.

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Abstract

Protein oxidation is known to compromise vital cellular functions. Therefore, invading pathogenic bacteria must resist damage inflicted by host defenses via reactive oxygen species. Using comparative genomics and experimental approaches, we provide multiple lines of evidence that proteins from pathogenic bacteria have acquired resistance to oxidative stress by an increased conformational stability. Representative pathogens exhibited higher survival upon HSP90 inhibition and a less-oxidationprone proteome. A proteome signature of the 46 pathogenic bacteria encompasses 14 physicochemical features related to increasing protein conformational stability. By purifying ten representative proteins, we demonstrate in vitro that proteins with a pathogen-like signature are more resistant to oxidative stress as a consequence of their increased conformational stability. A compositional signature of the pathogens’ proteomes allowed the design of protein fragments more resilient to both unfolding and carbonylation, validating the relationship between conformational stability and oxidability with implications for synthetic biology and antimicrobial strategies. Protein carbonylation has been associated not only with protein quality and cellular deterioration but also with a large number of age–related disorders and senescence. The involvement of protein chaperones in aging is intriguing and their potential contribution has, so far, been attributed solely to their central role in proteostasis. Here we show that four protein chaperones from different cellular compartments extend replicative lifespan (RLS) in budding yeast by a common mechanism akin to caloric restriction. The RLS extension relies on the increased direct activation of Snf1 kinase by Hsp90, thereby bypassing the signal on the environmental glucose level. The chaperone-related RLS extension is accompanied by the respiratory chain uncoupling. A genomic approach confirmed the repression of glycolysis and translation, as well as activation of gluconeogenesis and fatty acid oxidation. Our results set a novel paradigm for the role of protein chaperones: by modulation of the chaperone expression level one can affect cellular metabolic features, and consequently, modify lifespan. We expect the described mechanism to open new avenues for research in aging and age-related diseases.

Item Type: Thesis (Doctoral thesis)
Keywords: protein carbonylation, oxidative stress, conformational stability, replicative lifespan, chaperones
Supervisor: Radman, Miroslav
Date: 2016
Number of Pages: 124
Subjects: NATURAL SCIENCES > Biology
Divisions: Faculty of Science > Department of Biology
Depositing User: Grozdana Sirotic
Date Deposited: 05 Jul 2016 13:30
Last Modified: 05 Jul 2016 13:30
URI: http://digre.pmf.unizg.hr/id/eprint/4953

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