AAA proteins

Last updated
ATPases associated with diverse cellular activities
PDB 1nsf EBI.jpg
Structure of N-ethylmaleimide-sensitive factor. [1]
Identifiers
SymbolAAA
Pfam PF00004
Pfam clan CL0023
InterPro IPR003959
PROSITE PDOC00572
SCOP2 1nsf / SCOPe / SUPFAM
CDD cd00009
Membranome 74
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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]

Contents

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

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.

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. [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.

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 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)

AFG3L2; ATAD1; ATAD2; ATAD2B; ATAD3A; ATAD3B; ATAD3C; ATAD5; BCS1L; CHTF18; CLBP; CLPP; CLPX; FIGN; FIGNL1; FIGNL2; IQCA1; KATNA1; KATNAL1; KATNAL2; LONP1; LONP2; MDN1; NSF; NVL; ORC1; ORC4; PEX1; PEX6; PSMC1; PSMC2 (Nbla10058); PSMC3; PSMC4; PSMC5; PSMC6; RFC1; RFC2; RFC3; RFC4; RFC5; RUVBL1; RUVBL2; SPAST; SPATA5 (SPAF); SPATA5L1; SPG7; TRIP13; VCP; VPS4A; VPS4B; WRNIP1; YME1L1 (FTSH); [10]

Torsins

TOR1A; TOR1B; TOR2A; TOR3A; TOR4A; [11]

Other

AK6 (CINAP); [12] CDC6;

Pseudogenes

AFG3L1P; [13]

Further reading

Related Research Articles

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<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade unnecessary or damaged proteins by proteolysis

Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">Hsp90</span> Heat shock proteins with a molecular mass around 90kDa

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<span class="mw-page-title-main">ATP-binding cassette transporter</span> Gene family

The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

Katanin is a microtubule-severing AAA protein. It is named after the Japanese sword called a katana. Katanin is a heterodimeric protein first discovered in sea urchins. It contains a 60 kDa ATPase subunit, encoded by KATNA1, which functions to sever microtubules. This subunit requires ATP and the presence of microtubules for activation. The second 80 kDA subunit, encoded by KATNB1, regulates the activity of the ATPase and localizes the protein to centrosomes. Electron microscopy shows that katanin forms 14–16 nm rings in its active oligomerized state on the walls of microtubules.

<span class="mw-page-title-main">HslVU</span> Class of bacterial heat shock proteins

The heat shock proteins HslV and HslU are expressed in many bacteria such as E. coli in response to cell stress. The hslV protein is a protease and the hslU protein is an ATPase; the two form a symmetric assembly of four stacked rings, consisting of an hslV dodecamer bound to an hslU hexamer, with a central pore in which the protease and ATPase active sites reside. The hslV protein degrades unneeded or damaged proteins only when in complex with the hslU protein in the ATP-bound state. HslV is thought to resemble the hypothetical ancestor of the proteasome, a large protein complex specialized for regulated degradation of unneeded proteins in eukaryotes, many archaea, and a few bacteria. HslV bears high similarity to core subunits of proteasomes.

<span class="mw-page-title-main">PSMC3</span> Enzyme found in humans

26S protease regulatory subunit 6A, also known as 26S proteasome AAA-ATPase subunit Rpt5, is an enzyme that in humans is encoded by the PSMC3 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">ATP-binding domain of ABC transporters</span> Water-soluble domain of transmembrane ABC transporters

In molecular biology, ATP-binding domain of ABC transporters is a water-soluble domain of transmembrane ABC transporters.

<span class="mw-page-title-main">P-type ATPase</span>

The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon their ability to catalyze auto- (or self-) phosphorylation (hence P) of a key conserved aspartate residue within the pump and their energy source, adenosine triphosphate (ATP). In addition, they all appear to interconvert between at least two different conformations, denoted by E1 and E2. P-type ATPases fall under the P-type ATPase (P-ATPase) Superfamily (TC# 3.A.3) which, as of early 2016, includes 20 different protein families.

<span class="mw-page-title-main">Valosin-containing protein</span> Protein-coding gene in the species Homo sapiens

Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase also known as p97 in mammals and CDC48 in S. cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.

<span class="mw-page-title-main">PSMC5</span> Enzyme found in humans

26S protease regulatory subunit 8, also known as 26S proteasome AAA-ATPase subunit Rpt6, is an enzyme that in humans is encoded by the PSMC5 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD4</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 4, also as known as 26S Proteasome Regulatory Subunit Rpn10, is an enzyme that in humans is encoded by the PSMD4 gene. This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.

<span class="mw-page-title-main">PSMC2</span> Enzyme found in humans

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. Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMC4</span> Enzyme found in humans

26S protease regulatory subunit 6B, also known as 26S proteasome AAA-ATPase subunit Rpt3, is an enzyme that in humans is encoded by the PSMC4 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD2</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 2, also as known as 26S Proteasome Regulatory Subunit Rpn1, is an enzyme that in humans is encoded by the PSMD2 gene.

<span class="mw-page-title-main">VPS24</span> Protein-coding gene in the species Homo sapiens

Charged multivesicular body protein 3 is a protein that in humans is encoded by the VPS24 gene.

<span class="mw-page-title-main">VPS4A</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting-associated protein 4A is a protein that in humans is encoded by the VPS4A gene.

<span class="mw-page-title-main">VPS25</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein-sorting-associated protein 25 is a protein that in humans is encoded by the VPS25 gene.

The endosomal sorting complexes required for transport (ESCRT) machinery is made up of cytosolic protein complexes, known as ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III. Together with a number of accessory proteins, these ESCRT complexes enable a unique mode of membrane remodeling that results in membranes bending/budding away from the cytoplasm. These ESCRT components have been isolated and studied in a number of organisms including yeast and humans. A eukaryotic signature protein, the machinery is found in all eukaryotes and some archaea.

Eps15 homology domain-containing protein 3, abbreviated as EHD3 and also known as PAST3, is a protein encoded by the EHD3 gene. It has been observed in humans, mice and rats. It belongs to the EHD protein family, a group of four membrane remodeling proteins related to the Dynamin superfamily of large GTPases. Although the four of them are 70-80% amino acid identical, they all have different locations. Its main function is related to endocytic transport.

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. 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. 1 2 3 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. 1 2 3 4 5 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. 1 2 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. 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.
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