AAA proteins
Encyclopedia
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.
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.
, microtubule
dynamics, intracellular transport, flagellar and ciliary beating, disassembly of protein complexes and protein aggregates.
s in the AAA-domains as well as in the N-domains. These motions can be transmitted to substrate protein.
s. 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.
). 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.
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
;
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
of approximately 230 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. This is a large, functionally diverse protein family
Protein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
belonging to the AAA+ superfamily of ring-shaped P-loop NTPases
Nucleoside triphosphate
Nucleoside triphosphate is a nucleoside with three phosphates. Natural nucleoside triphosphates include adenosine triphosphate , guanosine triphosphate , cytidine triphosphate , 5-methyluridine triphosphate , and uridine triphosphate . These terms refer to those nucleoside triphosphates that...
, 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
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
, provided by ATP hydrolysis
ATP hydrolysis
ATP hydrolysis is the reaction by which chemical energy that has been stored and transported in the high-energy phosphoanhydridic bonds in ATP is released, for example in the muscles, to produce work. The product is ADP and an inorganic phosphate, orthophosphate...
, 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
Walker motifs
The Walker A and Walker B motifs are protein sequence motifs. These were first reported in ATP-binding proteins by Walker and co-workers in 1982.-Walker A motif:...
. 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 replicationReplication
Replication may refer to:Science* Replication is one of the main principles of the scientific method, a.k.a. reproducibility** Replication , the repetition of a test or complete experiment...
, microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
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 changeConformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
s 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 eukaryoteEukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s. 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 (ERADERAD
Endoplasmic-reticulum-associated protein degradation designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome....
). 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
BCS1L
-Further reading:...
; CDC6
CDC6
Cell division control protein 6 homolog is a protein that in humans is encoded by the CDC6 gene.-Interactions:CDC6 has been shown to interact with ORC1L, ORC2L, Cyclin A2, PPP2R3B, MCM3, PPP2R3A, MCM7 and PSKH1.-Further reading:...
; CHTF18
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, RFC2, RFC3, PCNA, RFC4 and RFC5.-Further reading:...
; CINAP; FIGN; FIGNL1; FTSH;
IQCA; KATNA1
KATNA1
Katanin p60 ATPase-containing subunit A1 is an enzyme that in humans is encoded by the KATNA1 gene.-Further reading:...
; KATNAL1; KATNAL2; LONP1
LONP1
Lon protease homolog, mitochondrial is an enzyme that in humans is encoded by the LONP1 gene.-Further reading:...
; LONP2; NSF
N-ethylmaleimide sensitive fusion protein
N-ethylmaleimide-sensitive factor, also known as NSF or N-ethylmaleimide sensitive fusion proteins, is an enzyme which in humans is encoded by the NSF gene.- Function :...
; NVL
NVL
In Oracle/PLSQL, the NVL function lets you substitute a value when a null value is encountered.The syntax for the NVL function is:*NVL string1 is the string to test for a null value. replace_with is the value returned if string1 is null.Both parameters of the function have to be of the same data type...
;
Nbla10058; ORC1L; PEX1
PEX1
Peroxisome biogenesis factor 1, also known as PEX1, is a protein which in humans is encoded by the PEX1 gene.This gene encodes a member of the AAA protein family, a large group of ATPases associated with diverse cellular activities...
; PEX6
PEX6
Peroxisome assembly factor 2 is a protein that in humans is encoded by the PEX6 gene.-Interactions:PEX6 has been shown to interact with PEX1 and PEX26.-External Links:* *...
; PSMC1
PSMC1
26S protease regulatory subunit 4 is an enzyme that in humans is encoded by the PSMC1 gene.-Interactions:PSMC1 has been shown to interact with PSMD2 and PSMC2.-Further reading:...
; PSMC2
PSMC2
26S protease regulatory subunit 7 is an enzyme that in humans is encoded by the PSMC2 gene.-Interactions:PSMC2 has been shown to interact with PSMD5, PSMC1, NDC80 and PSMC4.-Further reading:...
; PSMC3
PSMC3
26S protease regulatory subunit 6A is an enzyme that in humans is encoded by the PSMC3 gene.-Interactions:PSMC3 has been shown to interact with PSMC5 and Von Hippel-Lindau tumor suppressor.-Further reading:...
; PSMC4
PSMC4
26S protease regulatory subunit 6B is an enzyme that in humans is encoded by the PSMC4 gene.-Interactions:PSMC4 has been shown to interact with PSMD13, PSMD10, PSMC2 and PSMC5.-Further reading:...
;
PSMC5
PSMC5
26S protease regulatory subunit 8 is an enzyme that in humans is encoded by the PSMC5 gene.-Interactions:PSMC5 has been shown to interact with XPB, Sp1 transcription factor, PSMC3 and PSMC4.-Further reading:...
; PSMC6
PSMC6
26S protease regulatory subunit S10B is an enzyme that in humans is encoded by the PSMC6 gene.-Further reading:...
; RFC1
RFC1
Replication factor C subunit 1 is a protein that in humans is encoded by the RFC1 gene.-Interactions:RFC1 has been shown to interact with BRD4, HDAC1, RFC3, RELA and PCNA.-Further reading:...
; RFC2
RFC2
Replication factor C subunit 2 is a protein that in humans is encoded by the RFC2 gene.-Interactions:RFC2 has been shown to interact with BRD4, CHTF18, PCNA, RFC4 and RFC5.-Further reading:...
; RFC4
RFC4
Replication factor C subunit 4 is a protein that in humans is encoded by the RFC4 gene.-Interactions:RFC4 has been shown to interact with BRD4, RFC2, RFC3, CHTF18, PCNA and RFC5.-Further reading:...
; RFC5
RFC5
Replication factor C subunit 5 is a protein that in humans is encoded by the RFC5 gene.-Interactions:RFC5 has been shown to interact with BRD4, RFC2, PCNA, RFC4 and CHTF18.-Further reading:...
; RUVBL1; RUVBL2
RUVBL2
RuvB-like 2 , also known as RUVBL2, is a human gene coding for a protein belonging to the AAA+ family of proteins.-Interactions:RUVBL2 has been shown to interact with RuvB-like 1 and Activating transcription factor 2.-Further reading:...
;
SPAF; SPAST; SPATA5L1; SPG7
SPG7
Paraplegin is a protein that in humans is encoded by the SPG7 gene.-External Links:* -Further reading:...
; TRIP13
TRIP13
Thyroid receptor-interacting protein 13 is a protein that in humans is encoded by the TRIP13 gene.-Interactions:TRIP13 has been shown to interact with MAD2L1BP.-Further reading:...
; VCP
Valosin-containing protein
Transitional endoplasmic reticulum ATPase also known as valosin-containing protein is an enzyme that in humans is encoded by the VCP gene.- Function :...
; VPS4A
VPS4A
Vacuolar protein sorting-associated protein 4A is a protein that in humans is encoded by the VPS4A gene.-Further reading:...
; VPS4B
VPS4B
Vacuolar protein sorting-associated protein 4B is a protein that in humans is encoded by the VPS4B gene.-Further reading:...
;
WRNIP1
WRNIP1
ATPase WRNIP1 is an enzyme that in humans is encoded by the WRNIP1 gene.-Interactions:WRNIP1 has been shown to interact with Werner syndrome ATP-dependent helicase.-External links:...
; YME1L1
YME1L1
ATP-dependent metalloprotease YME1L1 is an enzyme that in humans is encoded by the YME1L1 gene.-Further reading:...
;