ААА протеиндері: құрылымы, функциясы және биологиялық ролі

Protein family

AAA (ATPases Associated with diverse cellular Activities) proteins are a large group of 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. AAA proteins couple chemical energy provided by ATP hydrolysis to conformational changes which are transduced into mechanical force exerted on a macromolecular substrate. Members of the AAA family are found in all organisms 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, 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. 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.

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.

Dyneins, one of the three major classes of motor protein, are AAA proteins which couple their ATPase activity to molecular motion along microtubules. 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.

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.

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