AAA⁺: A Class of Chaperone-Like ATPases Associated with the Assembly, Operation, and Disassembly of Protein Complexes

TLDR

AAA+ ATPases are widespread, including regulatory subunits of proteases, DNA replication factors, transcription regulators, and motor proteins, and their hexameric structure often functions as a channel for nucleic acids, facilitating assembly, operation, or disassembly of protein complexes. The authors used iterative database searches, multiple sequence alignment, and structural comparison to the clamp loader δ′ subunit and NSF hexamerization component to identify and characterize the AAA+ class. This analysis revealed that AAA+ sequences are far more common than previously thought, that the class is ancient with extensive functional divergence before the major life divisions, and that structural insights explain their chaperone‑like roles.

Abstract

Using a combination of computer methods for iterative database searches and multiple sequence alignment, we show that protein sequences related to the AAA family of ATPases are far more prevalent than reported previously. Among these are regulatory components of Lon and Clp proteases, proteins involved in DNA replication, recombination, and restriction (including subunits of the origin recognition complex, replication factor C proteins, MCM DNA-licensing factors and the bacterial DnaA, RuvB, and McrB proteins), prokaryotic NtrC-related transcription regulators, the Bacillus sporulation protein SpoVJ, Mg 2+ , and Co 2+ chelatases, the Halobacterium GvpN gas vesicle synthesis protein, dynein motor proteins, TorsinA, and Rubisco activase. Alignment of these sequences, in light of the structures of the clamp loader δ′ subunit of Escherichia coli DNA polymerase III and the hexamerization component of N -ethylmaleimide-sensitive fusion protein, provides structural and mechanistic insights into these proteins, collectively designated the AAA + class. Whole-genome analysis indicates that this class is ancient and has undergone considerable functional divergence prior to the emergence of the major divisions of life. These proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes. The hexameric architecture often associated with this class can provide a hole through which DNA or RNA can be thread; this may be important for assembly or remodeling of DNA–protein complexes.