AAA Proteins
   HOME

TheInfoList



OR:

AAA (ATPases Associated with diverse cellular Activities) proteins (speak: triple-A ATPases) are a large group of
protein family A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be ...
sharing a common conserved module of approximately 230
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
residues. This is a large, functionally diverse
protein family A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be ...
belonging to the AAA+
protein superfamily A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology (biology), homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if n ...
of ring-shaped
P-loop The Walker A and Walker B motifs are protein sequence motifs, known to have highly conserved three-dimensional structures. These were first reported in ATP-binding proteins by Walker and co-workers in 1982. Of the two motifs, the A motif is ...
NTPases, which exert their activity through the energy-dependent
remodeling Renovation (also called remodeling) is the process of improving broken, damaged, or outdated structures. Renovations are typically done on either commercial or residential buildings. Additionally, renovation can refer to making something new, o ...
or translocation of macromolecules. AAA proteins couple chemical energy provided by
ATP hydrolysis ATP hydrolysis is the catabolic reaction process by which chemical energy that has been stored in the high-energy phosphoanhydride bonds in adenosine triphosphate (ATP) is released after splitting these bonds, for example in muscles, by produ ...
to conformational changes which are transduced into mechanical force exerted on a
macromolecular A macromolecule is a "molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass." Polymers are physi ...
substrate. AAA proteins are functionally and organizationally diverse, and vary in activity, stability, and mechanism. Members of the AAA family are found in all organisms and they are essential for many cellular functions. They are involved in processes such as
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
, protein degradation,
membrane fusion In membrane biology, fusion is the process by which two initially distinct lipid bilayers merge their hydrophobic cores, resulting in one interconnected structure. If this fusion proceeds completely through both leaflets of both bilayers, an aqueou ...
, microtubule severing, peroxisome biogenesis,
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
and the
regulation of gene expression Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...
.


Structure

The AAA proteins contain two domains, an N-terminal alpha/beta domain that binds and hydrolyzes nucleotides (a Rossmann fold) and a C-terminal alpha-helical domain. The N-terminal domain is 200-250 amino acids long and contains Walker A and Walker B motifs, and is shared in common with other P-loop NTPases, the superfamily which includes the AAA family. Most AAA proteins have additional domains that are used for
oligomerization In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
, substrate binding and/or regulation. These domains can lie N- or C-terminal to the AAA module.


Classification

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.


Evolutionary relationships

AAA proteins are divided into seven basic
clade In biology, a clade (), also known as a Monophyly, monophyletic group or natural group, is a group of organisms that is composed of a common ancestor and all of its descendants. Clades are the fundamental unit of cladistics, a modern approach t ...
s, 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.


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. 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 change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...
s 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 In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they a ...
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.


Prokaryotic AAAs

AAA proteins are not restricted to
eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s. Prokaryotes have AAA which combine chaperone with
proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...
activity, for example in ClpAPS complex, which mediates protein degradation and recognition in ''
E. coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...
''. The basic recognition of proteins by AAAs is thought to occur through unfolded
protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
s 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 In membrane biology, fusion is the process by which two initially distinct lipid bilayers merge their hydrophobic cores, resulting in one interconnected structure. If this fusion proceeds completely through both leaflets of both bilayers, an aqueou ...
,
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
,
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
dynamics, intracellular transport, transcriptional activation, protein refolding, disassembly of protein complexes and protein aggregates.


Molecular motion

Dynein Dyneins are a family of cytoskeletal motor proteins (though they are actually protein complexes) that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargo ...
s, one of the three major classes of
motor protein Motor proteins are a class of molecular motors that can move along the cytoskeleton of cells. They do this by converting chemical energy into mechanical work by the hydrolysis of ATP. Cellular functions Motor proteins are the driving force b ...
, are AAA proteins which couple their ATPase activity to molecular motion along
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
. 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 The endosomal sorting complexes required for transport (ESCRT) proteins are part of a group of machines inside cells that help sort and move other proteins. One of their main jobs is to form structures called multivesicular bodies (MVBs) which help ...
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.


Proteasome functions

AAA proteases use the energy from ATP hydrolysis to translocate a protein inside the proteasome for degradation. Cdc48p/p97 functions as a hexameric AAA+ ATPase that provides the mechanical force necessary for substrate dislocation. Its activity is tightly regulated by ATP binding and hydrolysis, which induce conformational changes required for protein unfolding and extraction. The HbYX motif plays a crucial role in regulating this process by mediating interactions between Cdc48p/p97 and downstream effectors such as the 20S proteasome or specific cofactors (e.g., Ufd1/Npl4). This interaction facilitates substrate transfer from Cdc48p/p97 to the proteasome, ensuring efficient protein degradation. Given its pivotal role in protein homeostasis, Cdc48p/p97 has been implicated in a wide range of cellular processes beyond ERAD, including autophagy, mitochondrial quality control, and DNA repair. The dysregulation of its function, particularly through mutations affecting the ATPase domain or HbYX-mediated interactions, has been linked to neurodegenerative diseases and cancer.


Human proteins containing this domain


AAA ATPase family (HGNC)

AFG3L2; ATAD1; ATAD2; ATAD2B; ATAD3A; ATAD3B; ATAD3C; ATAD5; BCS1L;
CHTF18 Chromosome transmission fidelity protein 18 homolog is a protein that in humans is encoded by the ''CHTF18'' gene. Interactions CHTF18 has been shown to interact with: * DCC1, * PCNA, * RFC2, * RFC3 Replication factor C subunit 3 is ...
; CLBP; CLPP; CLPX; FIGN; FIGNL1; FIGNL2; IQCA1;
KATNA1 Katanin p60 ATPase-containing subunit A1 is an enzyme that in humans is encoded by the ''KATNA1'' gene. Microtubules, polymers of alpha and beta tubulin subunits, form the mitotic spindle of a dividing cell and help to organize membranous organel ...
; KATNAL1; KATNAL2; LONP1; LONP2; MDN1;
NSF NSF may stand for: Political organizations *National Socialist Front, a Swedish National Socialist party *NS-Frauenschaft, the women's wing of the former German Nazi party * National Students Federation, a leftist Pakistani students' political g ...
; NVL;
ORC1 Origin recognition complex subunit 1 is a protein that in humans is encoded by the ORC1 gene. It is closely related to CDC6, and both are the same protein in archaea. Function The origin recognition complex (ORC) is a highly conserved six s ...
;
ORC4 Origin recognition complex subunit 4 is a protein that in humans is encoded by the ORC4 (ORC4L) gene. Function The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA repli ...
; PEX1; PEX6;
PSMC1 26S protease regulatory subunit 4, also known as 26S proteasome AAA-ATPase subunit Rpt2, is an enzyme that in humans is encoded by the ''PSMC1'' gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. ...
;
PSMC2 26S protease regulatory subunit 7, also known as 26S proteasome AAA-ATPase subunit Rpt1, is an enzyme that in humans is encoded by the ''PSMC2'' gene This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. ...
(Nbla10058); PSMC3; PSMC4; PSMC5; PSMC6; RFC1; RFC2;
RFC3 Replication factor C subunit 3 is a protein that in humans is encoded by the ''RFC3'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA t ...
; RFC4; RFC5; RUVBL1;
RUVBL2 RuvB-like 2 (E. coli), also known as RUVBL2, is a human gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a ...
; SPAST; SPATA5 (SPAF); SPATA5L1; SPG7; TRIP13; VCP; VPS4A; VPS4B; WRNIP1; YME1L1 (FTSH);


Torsins

TOR1A; TOR1B; TOR2A; TOR3A; TOR4A;


Other

AK6 (CINAP);
CDC6 Cell division control protein 6 homolog is a protein that in humans is encoded by the ''CDC6'' gene. The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. ...
;


Pseudogenes

AFG3L1P;


Further reading

* *


References

{{DEFAULTSORT:Aaa Proteins Protein domains Protein families Protein superfamilies Single-pass transmembrane proteins