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Stress related proteases in Caulobacter crescentus

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

REDDY, MICHAEL K

项目受资助机构

UNIVERSITY OF MASSACHUSETTS AMHERST

立项年度

2015

立项时间

未公开

项目编号

3R01GM111706-01S1

项目级别

国家级

研究期限

未知 / 未知

受资助金额

35628.00美元

学科

GENETICS

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

CHIEN, PETER

参与机构

NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

项目标书摘要：DESCRIPTION (provided by applicant): Bacteria use energy dependent proteases to respond to stressful conditions. These proteases serve a dual role: destroying aberrant, potentially toxic, damaged proteins and generating stress responsive signals through degradation of regulatory factors. Cells often arrest replication in response to stress, but how regulated proteolysis contributes to cell cycle arrest in bacteria is currently poorly understood. This proposal addresses how stress related proteases target replication factors using a combination of biochemical, genetic and proteomic approaches, specifically focusing on proteases and replication factors from the model bacteria Caulobacter crescentus. Aims 1 and 2 determine how misfolded proteins generated during proteotoxic stress directly stimulate the Lon protease to destroy the replication initiator DnaA and cause growth arrest during stress. Aims 3 and 4 focus on how partial processing of the clamp loader subunit DnaX by the ClpXP protease is critical for replication stress tolerance during DNA damage. Because these proteases and replication factors are highly conserved throughout all bacteria, these results will impact our general understanding of replication, proteolysis, and stress tolerance. The critical role of these proteases in bacterial virulence and pathogenicity, together with the universal requirement for these proteases in bacterial stress responses, suggests that they are excellent targets for development of new antibiotic strategies that are of immediate human health need.

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  • 1.Regulated Proteolysis in Bacteria

    • 关键词：
    • ATP-DEPENDENT PROTEASES; SPECIFICITY-ENHANCING FACTOR; CELL-CYCLE PROGRESSION; AAA PLUS PROTEASE; ESCHERICHIA-COLI; LON PROTEASE; INORGANIC POLYPHOSPHATE; DNA-BINDING; RNA-POLYMERASE; DEGRADATION
    • Mahmoud, Samar A.;Chien, Peter
    • 《ANNUAL REVIEW OF BIOCHEMISTRY, VOL 87》
    • 2018年
    • 会议

    Regulated proteolysis is a vital process that affects all living things. Bacteria use energy-dependent AAA+ proteases to power degradation of misfolded and native regulatory proteins. Given that proteolysis is an irreversible event, specificity and selectivity in degrading substrates are key. Specificity is often augmented through the use of adaptors that modify the inherent specificity of the proteolytic machinery. Regulated protein degradation is intricately linked to quality control, cell-cycle progression, and physiological transitions. In this review, we highlight recent work that has shed light on our understanding of regulated proteolysis in bacteria. We discuss the role AAA+ proteases play during balanced growth as well as how these proteases are deployed during changes in growth. We present examples of how protease selectivity can be controlled in increasingly complex ways. Finally, we describe how coupling a core recognition determinant to one or more modifying agents is a general theme for regulated protein degradation.

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