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11  structures 566  species 5  interactions 3623  sequences 349  architectures

Family: AAA_9 (PF12781)

Summary: ATP-binding dynein motor region D5

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AAA proteins Edit Wikipedia article

For other uses see AAA (disambiguation)

ATPases associated with diverse cellular activities (AAA)
PDB 1nsf EBI.jpg
Structure of N-ethylmaleimide-sensitive factor.[1]
Identifiers
Symbol AAA
Pfam PF00004
Pfam clan CL0023
InterPro IPR003959
PROSITE PDOC00572
SCOP 1nsf
SUPERFAMILY 1nsf
CDD cd00009

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.[2][3]

AAA proteins couple chemical energy provided by ATP hydrolysis to conformational changes which are transduced into mechanical force exerted on a macromolecular substrate.[4]

AAA proteins are functionally and organizationally diverse, and vary in activity, stability, and mechanism.[4] Members of the AAA family are found in all organisms[5] and they are essential for many cellular functions. They are involved in processes such as DNA replication, protein degradation, membrane fusion, microtubule severing, peroxisome biogenesis, signal transduction and the regulation of gene expression.

Structure and classification

The AAA+ domain contains two subdomains, an N-terminal alpha/beta domain that binds and hydrolyzes nucleotides (a Rossman fold) and a C-terminal alpha-helical domain.[5] The N-terminal domain is 200-250 amino acids long and contains Walker A and Walker B motifs,[5] and is shared in common with other P-loop NTPases, the superfamily which includes the AAA+ family.[6] 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.

While the classical AAA family was based on motifs, the family has been expanded using structural information and is now termed the AAA+ family.[5]

Evolutionary relationships

AAA+ proteins are divided into seven basic clades, based on secondary structure elements included within or near the core AAA+ fold: clamp loader, initiator, classic, superfamily III helicase, HCLR, H2-insert, and PS-II insert.[4]

Quaternary structure

AAA ATPases assemble into oligomeric assemblies (often homo-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.[7]

The central pore may 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.

Molecular mechanism

ATP hydrolysis by AAA+ ATPases is proposed to involve nucleophilic attack on the ATP gamma-phosphate by an activated water molecule, leading to movement of the N-terminal and C-terminal AAA+ subdomains relative to each other. This movement allows the exertion of mechanical force, amplified by other ATPase domains within the same oligomeric structure. The additional domains in the protein allow for regulation or direction of the force towards different goals.[6]

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.

Functions

AAA+ proteins are involved in protein degradation, membrane fusion, DNA replication, microtubule dynamics, intracellular transport, transcriptional activation, protein refolding, disassembly of protein complexes and protein aggregates.[5][8]

Molecular motion

Dyneins, one of the three major classes of motor protein, are AAA proteins which couple their ATPase activity to molecular motion along microtubules.[9]

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.

Other functions

AAA proteases use the energy from ATP hydrolysis to translocate a protein inside the protease for degradation.

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

References

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ a b c Erzberger JP, Berger JM (2006). "Evolutionary relationships and structural mechanisms of AAA+ proteins". Annu. Rev. Biophys. Biomol. Struct. 35: 93–114. doi:10.1146/annurev.biophys.35.040405.101933. PMID 16689629. 
  5. ^ a b c d e 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. 
  6. ^ a b 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ Carter AP, Vale RD (February 2010). "Communication between the AAA+ ring and microtubule-binding domain of dynein". Biochem Cell Biol. 88 (1): 15–21. doi:10.1139/o09-127. PMID 20130675. 

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

ATP-binding dynein motor region D5 Provide feedback

The 380 kDa motor unit of dynein belongs to the AAA class of chaperone-like ATPases. The core of the 380 kDa motor unit contains a concatenated chain of six AAA modules, of which four correspond to the ATP binding sites with P-loop signatures described previously, and two are modules in which the P loop has been lost in evolution. This particular family is the D5 ATP-binding region of the motor, but has lost its P-loop [1].

Literature references

  1. Mocz G, Gibbons IR;, Structure. 2001;9:93-103.: Model for the motor component of dynein heavy chain based on homology to the AAA family of oligomeric ATPases. PUBMED:11250194 EPMC:11250194


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Domain organisation

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  Seed
(554)
Full
(3623)
Representative proteomes NCBI
(4924)
Meta
(92)
RP15
(856)
RP35
(1362)
RP55
(1779)
RP75
(2177)
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  Seed
(554)
Full
(3623)
Representative proteomes NCBI
(4924)
Meta
(92)
RP15
(856)
RP35
(1362)
RP55
(1779)
RP75
(2177)
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Curation and family details

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Seed source: Pfam-B_14 (release 24.0)
Previous IDs: none
Type: Domain
Author: Coggill P
Number in seed: 554
Number in full: 3623
Average length of the domain: 208.20 aa
Average identity of full alignment: 37 %
Average coverage of the sequence by the domain: 6.04 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild --amino -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.2 27.2
Trusted cut-off 27.2 27.2
Noise cut-off 27.1 27.1
Model length: 224
Family (HMM) version: 3
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Interactions

There are 5 interactions for this family. More...

AAA_8 GST_C DHC_N2 MT Dynein_heavy

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the AAA_9 domain has been found. There are 11 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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