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  • Review Article
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AAA+ proteins: have engine, will work

Nature Reviews Molecular Cell Biology volume 6, pages 519–529 (2005)Cite this article

Key Points

  • AAA+ proteins are ATPases associated with various cellular activities.

  • AAA+ proteins contain structurally conserved ATP-binding domains (AAA+ domains) that consist of N-terminal α/β and C-terminal α-helical subdomains. AAA+ domains are attached to various other domains and, in some cases, interact with adaptor proteins to generate the structural and functional diversity of the family. AAA+ domains function as oligomeric rings.

  • Mutations of conserved residues in AAA+ domains have predictable effects on nucleotide binding or hydrolysis, and have been successfully used to probe AAA+-protein function.

  • AAA+ proteins undergo conformational changes on nucleotide binding and hydrolysis; these changes can be large and seem to be responsible for the effects of these enzymes on their substrates.

  • AAA+ proteins are involved in many cellular processes, but seem to share the common behaviour of inducing conformational changes in target proteins. These conformational changes lead to substrate remodelling and, in some cases, perturb protein structure sufficiently to promote unfolding.

  • Key categories of AAA+-protein-mediated reactions include unfolding for proteolysis, the disassembly of protein aggregates, and the disassembly of otherwise stable protein complexes. All of these processes require the enzyme to hydrolyse ATP.

  • Mutations in AAA+ proteins are directly responsible for a number of inherited human diseases, including Zellweger's spectrum peroxisome-biogenesis disorders, early-onset torsion dystonia, hereditary spastic paraplegia, and inclusion-body myopathy with early-onset Paget's disease and frontotemporal dementia.

Abstract

The AAA+ (ATPases associated with various cellular activities) family is a large and functionally diverse group of enzymes that are able to induce conformational changes in a wide range of substrate proteins. The family's defining feature is a structurally conserved ATPase domain that assembles into oligomeric rings and undergoes conformational changes during cycles of nucleotide binding and hydrolysis. Here, we review the structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction.

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Figure 1: The organization of an AAA+ domain.
Figure 2: Structure of an AAA+ domain.
Figure 3: The structure of an AAA+ oligomer.
Figure 4: AAA+-protein function.

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  1. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Phyllis I. Hanson

  2. Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, 40536, Kentucky, USA

    Sidney W. Whiteheart

Authors
  1. Phyllis I. Hanson
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  2. Sidney W. Whiteheart
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Correspondence to Phyllis I. Hanson.

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DATABASES

Swiss-Prot

ClpA

ClpB

ClpP

ClpX

FtsH

Hsp104

Lon

FURTHER INFORMATION

Phyllis Hanson's laboratory

Glossary

WALKER-A AND -B MOTIFS

Conserved sequence elements that are characteristic of nucleotide-binding folds.

P-LOOP

A loop element of the Walker-A motif that is associated with the phoshates of bound nucleotides.

ROSSMAN FOLD

An α/β fold that is characteristic of nucleotide-binding domains.

HslU

The AAA+-protein component of the heat-shock-locus HslVU protease of bacteria and archaea.

NSF

(N-ethylmaleimide-sensitive factor or N-ethylmaleimide-sensitive fusion protein). It was originally discovered on the basis of its essential activity in transport between Golgi stacks.

p97/VCP

(97-kDa protein/valosin-containing protein). p97/VCP has been implicated in numerous cellular processes, but most clearly in handling ubiquitylated proteins en route to the proteasome.

THERMOTOLERANCE

A transient state of enhanced heat resistance that is induced by exposure to mild heat shock.

CHAMBERED PROTEASE

A barrel-shaped oligomeric proteolytic complex with restricted access to internal active sites.

ClpXP

Caseinolytic protease found in bacteria, which consists of a proteolytic ClpP barrel and a 'gatekeeping' AAA+ hexamer of ClpX.

ClpAP

ClpAP is similar to ClpXP and is also found in bacteria, but the 'gatekeeping' AAA+ hexamer is composed of ClpA.

FtsH

A membrane-anchored AAA protease in bacteria, which contains AAA and protease domains within a single polypeptide chain.

Lon

A soluble AAA protease in bacteria, which contains AAA and protease domains within a single polypeptide chain. It is important in cell stress responses.

26S PROTEASOME

The primary chambered protease in eukaryotes. Its name reflects its approximate sedimentation coefficient. It is composed of multicatalytic proteolytic (20S) and regulatory (19S) subcomplexes.

ClpP

The proteolytic component of bacterial chambered proteases, which consists of 14 proteolytic subunits.

GroEL TRAP

A mutant of the GroEL chaperonin that binds unfolded proteins but does not release them.

PRION

A proteinaceous infectious particle, which was discovered by Stanley Prusiner for its role in the transmission of infectious neurodegenerative disorders. Prions are conformationally modified proteins.

[PSI+]

An ordered aggregate of the yeast translation terminator Sup35, which is referred to as a yeast prion.

Hsp70 CHAPERONE SYSTEM

(70-kDa heat-shock-protein chaperone system). Conserved family of ∼70-kDa ATPases that are involved in protein folding. They cooperate with Hsp40 and nucleotide-exchange factors. Members include DnaK, DnaJ and GrpE in Escherichia coli and related proteins in higher organisms.

DNA TRANSPOSITION

The movement of mobile DNA elements or transposons by recombination.

Mu TRANSPOSOSOME

A complex containing the MuA transposase tetramer and the two ends of the Mu genomic DNA.

MuA TRANSPOSASE

A 75-kDa multidomain enzyme of a bacterial virus. It forms a homotetramer and promotes DNA recombination by catalysing donor DNA cleavage and strand transfer and joining at the target site.

SNAREs

(soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptors). Coiled-coil-forming proteins that are found on cellular membranes and that promote intracellular membrane fusion.

α-SNAP

(α-soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein). Recruits NSF to membranes and binds to SNARE proteins.

MULTIVESICULAR BODY

An endosome, usually a late endosome, that contains lumenal vesicles. The internal vesicles are thought to form by invagination and budding from the limiting membrane.

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Hanson, P., Whiteheart, S. AAA+ proteins: have engine, will work. Nat Rev Mol Cell Biol 6, 519–529 (2005). https://doi.org/10.1038/nrm1684

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