Mechanistic insights into bacterial AAA+ proteases and protein-remodelling machines

• Published in: Nature reviews. Microbiology 2016, Vol.14 (1), p.33-44
• Main Authors: Olivares, Adrian O., Baker, Tania A., Sauer, Robert T.
• Format: Article
• Language: English
• Subjects: 631/326/41/2536; 631/326/41/88; 631/337/474/2085; 631/535; Adenosine Triphosphate - metabolism; Archaea; Bacteria; Bacteria - chemistry; Bacteria - enzymology; Bacteria - genetics; Denaturation; Endopeptidase Clp - chemistry; Endopeptidase Clp - genetics; Endopeptidase Clp - metabolism; Infectious Diseases; Life Sciences; Macromolecular Substances - metabolism; Medical Microbiology; Microbiology; Models, Biological; Models, Molecular; Parasitology; Physiological aspects; Proteases; Protein Folding; Proteins; Proteolysis; review-article; Translocation; Virology
• ISSN: 1740-1526; 1740-1534
• DOI: 10.1038/nrmicro.2015.4

Key Points In ATP-dependent proteases, a ring-shaped AAA+ machine harnesses the chemical energy of ATP binding and hydrolysis to mechanically unfold target proteins by translocating them through an axial pore and into the degradation chamber of a self-compartmentalized peptidase Recognition of 'degron' sequences in specific target proteins involves the direct binding of amino-acid sequences to the axial pore of the AAA+ ring, binding of sequences to auxiliary domains and/or binding mediated by adaptor proteins. Degron sequences can be revealed or added to substrates by protein-modification reactions Novel antibiotics kill some bacteria by binding to the ClpP peptidase and transforming it into a rogue enzyme that indiscriminately degrades nascent polypeptides and unstructured cellular proteins Single-molecule optical trapping has directly visualized the unfolding and translocation activities of the ClpXP and ClpAP AAA+ proteases. These experiments and solution studies support a probabilistic model of AAA+ ring function and show that each power stroke has a constant — and typically low — probability of unfolding a stable protein domain Although protein degradation by AAA+ proteases is typically highly processive, multidomain substrates are sometimes only partially proteolysed, with the released products having new biological functions AAA+ enzymes can function independently of peptidases to solubilize aggregated proteins, to disassemble macromolecular complexes or to catalyse the incorporation of cofactors into enzymes AAA+ proteolytic machines unfold and degrade damaged and unneeded proteins in all domains of life. In this Review, Sauer and colleagues discuss the molecular mechanisms and structures of bacterial AAA+ machines, focusing on recent studies of ClpXP as a paradigm. To maintain protein homeostasis, AAA+ proteolytic machines degrade damaged and unneeded proteins in bacteria, archaea and eukaryotes. This process involves the ATP-dependent unfolding of a target protein and its subsequent translocation into a self-compartmentalized proteolytic chamber. Related AAA+ enzymes also disaggregate and remodel proteins. Recent structural and biochemical studies, in combination with direct visualization of unfolding and translocation in single-molecule experiments, have illuminated the molecular mechanisms behind these processes and suggest how remodelling of macromolecular complexes by AAA+ enzymes could occur without global denaturation. In this Review, we d