Summary: AAA domain
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AAA proteins Edit Wikipedia article
For other uses see AAA (disambiguation)
|ATPases associated with diverse cellular activities (AAA)|
|Structure of N-ethylmaleimide-sensitive factor.|
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 remodeling or translocation of macromolecules. These proteins are involved in a range of processes, including DNA replication, 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.
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 Walker B motifs. AAA proteins themselves belong to the superfamily of P-loop NTPases.
 Domain structure of AAA-type ATPases
All AAA+ proteins have a mixed alpha/beta domain that binds and hydrolyzes nucleotide. Most AAA+ proteins have a second domain that comprises the AAA+ module: an all alpha-helical domain, often called the lid domain, that is C-terminal of the alpha/beta domain. Most AAA+ proteins have additional domains that are used for oligomerization, substrate binding and/or regulation. These domains can lie N- or C-terminal to the AAA+ module.
Some classes of 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 Cdc48/p97). 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, intracellular transport, flagellar and ciliary beating, disassembly of protein complexes and protein aggregates.
 AAAs are often Hexamers
The physiologically active form of these enzymes is often a homo-hexamer. The hexameric enzymes have an overall shape that resembles a 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;
 Further reading
- Snider J, Thibault G, Houry WA (2008). "The AAA+ superfamily of functionally diverse proteins". Genome Biol. 9 (4): 216. doi:10.1186/gb-2008-9-4-216. PMC 2643927. PMID 18466635. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2643927/.
- Snider J, Houry WA (February 2008). "AAA+ proteins: diversity in function, similarity in structure". Biochem. Soc. Trans. 36 (Pt 1): 72–7. doi:10.1042/BST0360072. PMID 18208389.
- Tucker PA, Sallai L (December 2007). "The AAA+ superfamily--a myriad of motions". Curr. Opin. Struct. Biol. 17 (6): 641–52. doi:10.1016/j.sbi.2007.09.012. PMID 18023171.
- White SR, Lauring B (December 2007). "AAA+ ATPases: achieving diversity of function with conserved machinery". Traffic 8 (12): 1657–67. doi:10.1111/j.1600-0854.2007.00642.x. PMID 17897320.
- Hanson PI, Whiteheart SW (July 2005). "AAA+ proteins: have engine, will work". Nat. Rev. Mol. Cell Biol. 6 (7): 519–29. doi:10.1038/nrm1684. PMID 16072036.
- Yu RC, Hanson PI, Jahn R, Brünger AT (September 1998). "Structure of the ATP-dependent oligomerization domain of N-ethylmaleimide sensitive factor complexed with ATP". Nat. Struct. Biol. 5 (9): 803–11. doi:10.1038/1843. PMID 9731775.
- 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. doi:10.1016/j.jsb.2003.10.010. PMID 15037234.
- Lupas AN, Frickey T (2004). "Phylogenetic analysis of AAA proteins". J. Struct. Biol. 146 (1–2): 2–10. doi:10.1016/j.jsb.2003.11.020. PMID 15037233.
- Smith DM, Benaroudj N, Goldberg A (2006). "Proteasomes and their associated ATPases: A destructive combination". J. Struct. Biol. 156 (1): 72–83. doi:10.1016/j.jsb.2006.04.012. PMID 16919475.
AAA domain Provide feedback
This family includes a wide variety of AAA domains including some that have lost essential nucleotide binding residues in the P-loop.
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|Similarity to PfamA using HHSearch:||Mg_chelatase RNA_helicase AAA_16|
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|Number in seed:||125|
|Number in full:||1541|
|Average length of the domain:||341.70 aa|
|Average identity of full alignment:||25 %|
|Average coverage of the sequence by the domain:||52.08 %|
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search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
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