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264  structures 6164  species 13  interactions 52090  sequences 426  architectures

Family: AAA (PF00004)

Summary: ATPase family associated with various cellular activities (AAA)

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "AAA proteins". More...

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. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

ATPase family associated with various cellular activities (AAA) Provide feedback

AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].

Literature references

  1. Confalonieri F, Duguet M; , Bioessays 1995;17:639-650.: A 200-amino acid ATPase module in search of a basic function. PUBMED:7646486 EPMC:7646486

  2. Neuwald AF, Aravind L, Spouge JL, Koonin EV; , Genome Res 1999;9:27-43.: AAA+: A class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. PUBMED:9927482 EPMC:9927482


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003959

AAA ATPases (ATPases Associated with diverse cellular Activities) form a large protein family and play a number of roles in the cell including cell-cycle regulation, protein proteolysis and disaggregation, organelle biogenesis and intracellular transport. Some of them function as molecular chaperones, subunits of proteolytic complexes or independent proteases (FtsH, Lon). They also act as DNA helicases and transcription factors [PUBMED:17201069].

AAA ATPases belong to the AAA+ superfamily of ringshaped P-loop NTPases, which act via the energy-dependent unfolding of macromolecules [PUBMED:15037233, PUBMED:16828312]. There are six major clades of AAA domains (proteasome subunits, metalloproteases, domains D1 and D2 of ATPases with two AAA domains, the MSP1/katanin/spastin group and BCS1 and it homologues), as well as a number of deeply branching minor clades [PUBMED:15037233].

They 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 act upon a target substrate, either translocating or remodelling it [PUBMED:16919475].

They are found in all living organisms and share the common feature of the presence of a highly conserved AAA domain called the AAA module. This domain is responsible for ATP binding and hydrolysis. It contains 200-250 residues, among them there are two classical motifs, Walker A (GX4GKT) and Walker B (HyDE) [PUBMED:17201069].

The functional variety seen between AAA ATPases is in part due to their extensive number of accessory domains and factors, and to their variable organisation within oligomeric assemblies, in addition to changes in key functional residues within the ATPase domain itself.

More information about these proteins can be found at Protein of the Month: AAA ATPases [PUBMED:].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan P-loop_NTPase (CL0023), which has the following description:

AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].

The clan contains the following 198 members:

6PF2K AAA AAA-ATPase_like AAA_10 AAA_11 AAA_12 AAA_13 AAA_14 AAA_15 AAA_16 AAA_17 AAA_18 AAA_19 AAA_2 AAA_21 AAA_22 AAA_23 AAA_24 AAA_25 AAA_26 AAA_27 AAA_28 AAA_29 AAA_3 AAA_30 AAA_31 AAA_32 AAA_33 AAA_34 AAA_35 AAA_4 AAA_5 AAA_6 AAA_7 AAA_8 AAA_9 AAA_PrkA ABC_ATPase ABC_tran ABC_tran_2 Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arch_ATPase Arf ArgK ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 Bac_DnaA CbiA CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DEAD DEAD_2 DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DUF1253 DUF1611 DUF2075 DUF2478 DUF258 DUF2791 DUF2813 DUF3584 DUF463 DUF815 DUF853 DUF87 DUF927 Dynamin_N Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GTP_EFTU GTP_EFTU_D2 GTP_EFTU_D4 Gtr1_RagA Guanylate_kin GvpD HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD Herpes_Helicase Herpes_ori_bp Herpes_TK IIGP IPPT IPT IstB_IS21 KaiC KAP_NTPase Kinesin Kinesin-relat_1 Kinesin-related KTI12 LpxK MCM MEDS Mg_chelatase Mg_chelatase_2 MipZ Miro MMR_HSR1 MobB MukB MutS_V Myosin_head NACHT NB-ARC NOG1 NTPase_1 ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK Rad17 Rad51 Ras RecA ResIII RHD3 RHSP RNA12 RNA_helicase RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2_N Spore_IV_A SRP54 SRPRB Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulphotransf T2SE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6 Terminase_GpA Thymidylate_kin TIP49 TK TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind UPF0079 UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE YhjQ Zeta_toxin Zot

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(207)
Full
(52090)
Representative proteomes NCBI
(92205)
Meta
(29927)
RP15
(6957)
RP35
(12667)
RP55
(17600)
RP75
(20937)
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Format an alignment

  Seed
(207)
Full
(52090)
Representative proteomes NCBI
(92205)
Meta
(29927)
RP15
(6957)
RP35
(12667)
RP55
(17600)
RP75
(20937)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(207)
Full
(52090)
Representative proteomes NCBI
(92205)
Meta
(29927)
RP15
(6957)
RP35
(12667)
RP55
(17600)
RP75
(20937)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Family
Author: Sonnhammer ELL
Number in seed: 207
Number in full: 52090
Average length of the domain: 130.80 aa
Average identity of full alignment: 25 %
Average coverage of the sequence by the domain: 20.90 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.8 20.8
Trusted cut-off 20.8 20.8
Noise cut-off 20.7 20.7
Model length: 132
Family (HMM) version: 24
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 13 interactions for this family. More...

AAA_2 DNA_pol3_delta RuvB_C AAA Rep_fac_C Peptidase_M41 CDC48_2 Vps4_C Clp_N TIP49 CDC48_N RuvA_C RuvB_N

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 domain has been found. There are 264 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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