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AAA proteins



ATPase family associated with various cellular activities (AAA)
Identifiers
Symbol AAA
Pfam PF00004
InterPro IPR003959
SCOP 1nsf
Available PDB structures:

1jbkA:201-286 1qvrC:193-386 1ksfX:209-403 1r6bX:209-403 1xxhI:40-230 1njgB:40-230 1jr3C:40-230 1xxiD:40-230 1njfB:40-230 1lfsA:55-177 1iqpB:585-743 1in7A:53-232 1in5A:53-232 1in8A:53-232 1in6A:53-232 1j7kA:53-232 1in4A:53-232 1ixrC:40-236 1ixsB:40-236 1hqcA:40-236 1ypwB:513-700 1yq0C:513-700 1oz4B:513-700 1r7rA:513-700 1yqiA:513-700 1s3sE:240-424 1e32A:240-424 1lv7A:187-374 1iy0A:191-378 1ixzA:191-378 1iy2A:191-378 1iy1A:191-378 1xwiA:169-354 1nsf :538-571 1d2nA:538-571 1rkbA:5-35 1qzmA:491-545 1x37A:490-544


AAA or AAA+ is an abbreviation for ATPases Associated with diverse cellular Activities. They share a common conserved module of approximately 230 amino acid residues. This is a large, functionally diverse protein family belonging to the AAA+ superfamily of ring-shaped P-loop NTPases, which exert their activity through the energy-dependent unfolding of macromolecules[1][2]. These proteins are involved in a range of processes, including protein degradation, membrane fusion, microtubule severing, peroxisome biogenesis, signal transduction and the regulation of gene expression.

The characteristic of AAA proteins is the coupling of chemical energy by ATPase, provided by ATP hydrolysis, to mechanical force exerted on some macromolecular substrate. This usually requires a conformational change in the AAA protein in question.

AAA ATPases assemble into oligomeric assemblies (often hexamers) that form a ring-shaped structure with a central pore. These proteins produce a molecular motor that couples ATP binding and hydrolysis to changes in conformational states that can be propagated through the assembly in order to act upon a target substrate, either translocating or remodelling the substrate[3].

Members of the AAA family are found in all organisms and they are essential for many cellular functions.

One type of AAA Proteins are AAA Proteases, where the energy from ATP hydrolysis is used to translocate a Protein inside the Protease for degradation.

AAA-type ATPases constitute a large family of enzymes. AAA proteins are characterised by the presence of 200-250 amino-acid ATP-binding domains that contain Walker A and B motifs. AAA proteins themselves belong to the superfamily of P-loop NTPases.


Additional recommended knowledge

Contents

Domain structure of AAA-type ATPases

AAA proteins have an N-terminal Non-ATPase domain which is followed by either one or two AAA domains (D1 and D2). In some proteins with two AAA domains, both are evolutionarily well conserved (like in Cdc48p/97). In others, either the D2 domain (like in Pex1p and Pex6p) or the D1 domain (in Sec18p/NSF) is better conserved in evolution.

From AAA to AAA+

The classical AAA family has been expanded by inclusion of a number of more distantly related cellular regulators and termed AAA+ family of ATPases (112). AAA+ proteins are involved in protein degradation, membrane fusion, DNA replication, microtubule dynamics, disassembly of protein complexes and protein aggregates.

AAAs are mechanoenzymes that manipulate the structure of substrate proteins and thereby unfold them or disassemble protein complexes.

AAAs are often Hexamers

The physiologically active form of these enzymes is often an homo-hexamer. The hexameric enzymes have an overall shape that resembles a double-ring with a central pore that might be involved in substrate processing. In the hexameric configuration, the ATP-binding site is positioned at the interface between the subunits. Upon ATP binding and hydrolysis, AAA enzymes undergo conformational changes in the AAA-domains as well as in the N-domains. These motions can be transmitted to substrate protein.

Prokaryotic AAAs

AAA proteins are not restricted to eukaryotes. Prokaryotes have AAA which combine chaperone with proteolytic activity, for example in ClpAPS complex, which mediates protein degradation and recognition in E. coli. The basic recognition of proteins by AAAs is thought to occur through unfolded domains in the substrate protein. In HslU, a bacterial ClpX/ClpY homologue of the HSP100 family of AAA+ proteins, the N- and C-terminal subdomains move towards each other when nucleotides are bound and hydrolysed. The terminal domains are most distant in the nucleotide-free state and closest in the ADP-bound state. Thereby the opening of the central cavity is affected.

AAAs in protein transport

The AAA-type ATPase Cdc48p/p97 is perhaps the best-studied AAA protein. Misfolded secretory proteins are exported from the endoplasmic reticulum (ER) and degraded by the ER-associated degradation pathway (ERAD). Nonfunctional membrane and luminal proteins are extracted from the ER and degraded in the cytosol by proteasomes. Substrate retrotranslocation and extraction is assisted by the Cdc48p(Ufd1p/Npl4p) complex on the cytosolic side of the membrane. On the cytosolic side, the substrate is ubiquitinated by ER-based E2 and E3 enzymes before degradation by the 26S proteasome.

Targeting to multivesicular bodies

Multivesicular bodies are endosomal compartments that sort ubiquitinated membrane proteins by incorporating them into vesicles. This process involves the sequential action of three multiprotein complexes, ESCRT I to III (ESCRT standing for 'endosomal sorting complexes required for transport'). Vps4p is a AAA-type ATPase involved in this MVB sorting pathway. It had originally been identified as a ”class E” vps (vacuolar protein sorting) mutant and was subsequently shown to catalyse the dissociation of ESCRT complexes. Vps4p is anchored via Vps46p to the endosomal membrane. Vps4p assembly is assisted by the conserved Vta1p protein, which regulates its oligomerzation status and ATPase activity.

Human proteins containing this domain

AFG3L1; AFG3L2; AK6; ATAD1; ATAD2; ATAD2B; ATAD3A; ATAD3B; ATAD3C; BCS1L; CDC6; CHTF18; CINAP; FIGN; FIGNL1; FTSH; IQCA; KATNA1; KATNAL1; KATNAL2; LONP1; LONP2; NSF; NVL; Nbla10058; ORC1L; PEX1; PEX6; PSMC1; PSMC2; PSMC3; PSMC4; PSMC5; PSMC6; RFC1; RFC2; RFC4; RFC5; RUVBL1; RUVBL2; SPAF; SPAST; SPATA5L1; SPG7; TRIP13; VCP; VPS4A; VPS4B; WRNIP1; YME1L1;

References

  1. ^ Koonin EV, Aravind L, Leipe DD, Iyer LM (2004). "Evolutionary history and higher order classification of AAA+ ATPases". J. Struct. Biol. 146 (1-2): 11-31. PMID 15037234.
  2. ^ Lupas AN, Frickey T (2004). "Phylogenetic analysis of AAA proteins". J. Struct. Biol. 146 (1-2): 2-10. PMID 15037233.
  3. ^ Smith DM, Benaroudj N, Goldberg A (2006). "Proteasomes and their associated ATPases: A destructive combination". J. Struct. Biol.: -. PMID 16919475.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "AAA_proteins". A list of authors is available in Wikipedia.
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