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204  structures 6494  species 0  interactions 29830  sequences 502  architectures

Family: AAA_5 (PF07728)

Summary: AAA domain (dynein-related subfamily)

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

AAA proteins Edit Wikipedia article

ATPases associated with diverse cellular activities
PDB 1nsf EBI.jpg
Structure of N-ethylmaleimide-sensitive factor.[1]
Pfam clanCL0023

AAA proteins or ATPases Associated with diverse cellular Activities are a protein family sharing a common conserved module of approximately 230 amino acid residues. This is a large, functionally diverse protein family belonging to the AAA+ protein 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.


The AAA domain contains two subdomains, an N-terminal alpha/beta domain that binds and hydrolyzes nucleotides (a Rossmann 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 protein 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.


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 oligomerization status and ATPase activity.

Other functions

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

Human proteins containing this domain

AAA ATPase family (HGNC)





AK6 (CINAP);[12] CDC6;



Further reading


  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. S2CID 13261575.
  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. S2CID 27830342.
  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/ 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. PMC 2894566. PMID 20130675.
  10. ^ "Gene group: AAA ATPases (ATAD)". HUGO Gene Nomenclature Committee.
  11. ^ "Gene group: Torsins (TOR)". HUGO Gene Nomenclature Committee.
  12. ^ "Symbol report for AK6". HUGO Gene Nomenclature Committee.
  13. ^ "Symbol report for AFG3L1P". HUGO Gene Nomenclature Committee.

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.

AAA domain (dynein-related subfamily) Provide feedback

This Pfam entry includes some of the AAA proteins not detected by the PF00004 model.

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

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR011704

The ATPases Associated to a variety of cellular Activities (AAA) are a family distinguished by a highly conserved module of 230 amino acids [ PUBMED:7646486 ]. The highly conserved nature of this module across taxa suggests that it has a key cellular role. Members of the family are involved in diverse cellular functions including gene expression, peroxisome assembly and vesicle mediated transport. Although the role of this ATPase AAA domain is not, as yet, clear, the AAA+ superfamily of proteins to which the AAA ATPases belong has a chaperone-like function in the assembly, operation or disassembly of proteins [ PUBMED:9927482 ]. This ATPase domain includes some proteins not detected by the INTERPRO model.

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 245 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_5 AAA_6 AAA_7 AAA_8 AAA_9 AAA_PrkA ABC_ATPase ABC_tran ABC_tran_Xtn Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arf ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 ATPase ATPase_2 Bac_DnaA BCA_ABC_TP_C Beta-Casp bpMoxR BrxC_BrxD BrxL_ATPase Cas_Csn2 Cas_St_Csn2 CbiA CBP_BcsQ CDC73_C CENP-M CFTR_R CLP1_P CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CSM2 CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DEAD DEAD_2 divDNAB DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DO-GTPase1 DO-GTPase2 DUF1611 DUF2075 DUF2326 DUF2478 DUF257 DUF2813 DUF3584 DUF463 DUF4914 DUF5906 DUF6079 DUF815 DUF835 DUF87 DUF927 Dynamin_N Dynein_heavy Elong_Iki1 ELP6 ERCC3_RAD25_C Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GBP_C GpA_ATPase GpA_nuclease GTP_EFTU Gtr1_RagA Guanylate_kin GvpD_P-loop HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD HerA_C Herpes_Helicase Herpes_ori_bp Herpes_TK HydF_dimer HydF_tetramer Hydin_ADK IIGP IPPT IPT iSTAND IstB_IS21 KAP_NTPase KdpD Kinase-PPPase Kinesin KTI12 LAP1_C LpxK MCM MeaB MEDS Mg_chelatase Microtub_bd MipZ MMR_HSR1 MMR_HSR1_C MobB MukB Mur_ligase_M MutS_V Myosin_head NACHT NAT_N NB-ARC NOG1 NTPase_1 NTPase_P4 ORC3_N P-loop_TraG ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Ploopntkinase1 Ploopntkinase2 Ploopntkinase3 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK PSY3 Rad17 Rad51 Ras RecA ResIII RHD3_GTPase RhoGAP_pG1_pG2 RHSP RNA12 RNA_helicase Roc RsgA_GTPase RuvB_N SbcC_Walker_B SecA_DEAD Senescence Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2-rel_dom SpoIVA_ATPase Spore_III_AA SRP54 SRPRB SulA Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulfotransfer_4 Sulfotransfer_5 Sulphotransf SWI2_SNF2 T2SSE T4SS-DNA_transf TerL_ATPase Terminase_3 Terminase_6N Thymidylate_kin TIP49 TK TmcA_N TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind TsaE UvrB UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE YqeC Zeta_toxin Zot


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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: PfamB-136 (Release 14.0)
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Studholme DJ
Number in seed: 33
Number in full: 29830
Average length of the domain: 131.00 aa
Average identity of full alignment: 21 %
Average coverage of the sequence by the domain: 23.20 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.0 22.0
Trusted cut-off 22.0 22.0
Noise cut-off 21.9 21.9
Model length: 138
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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_5 domain has been found. There are 204 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 sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2K3W1 View 3D Structure Click here
A3KMH1 View 3D Structure Click here
A4IDZ9 View 3D Structure Click here
A7IHP6 View 3D Structure Click here
B0R0T1 View 3D Structure Click here
B0UFH4 View 3D Structure Click here
B8IMW6 View 3D Structure Click here
M9PHH0 View 3D Structure Click here
O31850 View 3D Structure Click here
O34885 View 3D Structure Click here
O53705 View 3D Structure Click here
P15005 View 3D Structure Click here
P31473 View 3D Structure Click here
P33348 View 3D Structure Click here
P43591 View 3D Structure Click here
P71922 View 3D Structure Click here
P9WPR3 View 3D Structure Click here
Q19346 View 3D Structure Click here
Q2G2J8 View 3D Structure Click here
Q382V8 View 3D Structure Click here
Q3J6B1 View 3D Structure Click here
Q44772 View 3D Structure Click here
Q49XL1 View 3D Structure Click here
Q4CY33 View 3D Structure Click here
Q4DRN5 View 3D Structure Click here
Q4DVV0 View 3D Structure Click here
Q4DZ77 View 3D Structure Click here
Q4E408 View 3D Structure Click here
Q4L6B6 View 3D Structure Click here
Q51481 View 3D Structure Click here
Q51664 View 3D Structure Click here
Q54IQ2 View 3D Structure Click here
Q5HPD3 View 3D Structure Click here
Q60389 View 3D Structure Click here
Q8CC88 View 3D Structure Click here
Q8F3Q5 View 3D Structure Click here
Q8I0E1 View 3D Structure Click here
Q9HHS9 View 3D Structure Click here
Q9HI16 View 3D Structure Click here