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Mechanistic insights into bacterial AAA+ proteases and protein-remodelling machines
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Journal Article
Mechanistic insights into bacterial AAA+ proteases and protein-remodelling machines
2016
Overview
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 discuss the structural and mechanistic features of AAA+ proteases and remodelling machines, focusing on the bacterial ClpXP and ClpX as paradigms. We also consider the potential of these enzymes as antibacterial targets and outline future challenges for the field.
Publisher
Nature Publishing Group UK,Nature Publishing Group
