期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 26, 页码 10490-10495出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1101084108
关键词
X-ray crystallography; protein quality control; oligomerization; PDZ domain; molecular switch
资金
- Helmholtz Zentrum Berlin fur Materialien und Energie
- Freie Universitat Berlin
- Humboldt-Universitat zu Berlin
- Max-Delbruck Centrum
- Leibniz-Institut fur Molekulare Pharmakologie
- European Commission (EC) [R II 3-CT-2004-506008, LSH-2005-037793]
- Deutsche Forschungsgemeinschaft Cluster of Excellence [EXC 306]
- Fonds der Chemischen Industrie
- Chinese Academy of Sciences [2010T1S6]
Proteases of the HtrA family are key factors dealing with folding stress in the periplasmatic compartment of prokaryotes. In Escherichia coli, the well-characterized HtrA family members DegS and DegP counteract the accumulation of unfolded outer-membrane proteins under stress conditions. Whereas DegS serves as a folding-stress sensor, DegP is a chaperone-protease facilitating refolding or degradation of defective outer-membrane proteins. Here, we report the 2.15-angstrom-resolution crystal structure of the second major chaperone-protease of the periplasm, DegQ from Legionella fallonii. DegQ assembles into large, cage-like 12-mers that form independently of unfolded substrate proteins. We provide evidence that 12-mer formation is essential for the degradation of substrate proteins but not for the chaperone activity of DegQ. In the current model for the regulation of periplasmatic chaper-one-proteases, 6-meric assemblies represent important protease-resting states. However, DegQ is unable to form such 6-mers, suggesting divergent regulatory mechanisms for DegQ and DegP. To understand how the protease activity of DegQ is controlled, we probed its functional properties employing designed protein variants. Combining crystallographic, biochemical, and mutagenic data, we present a mechanistic model that suggests how protease activity of DegQ 12-mers is intrinsically regulated and how deleterious proteolysis by free DegQ 3-mers is prevented. Our study sheds light on a previously uncharacterized component of the prokaryotic stress-response system with implications for other members of the HtrA family.
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