AAA+ ATPases

The AAA+ family of ATPases is an extension of the AAA (for ATPases associated with a variety of cellular activities) family, originally defined to include proteins with a common ~200 residue ATPase core that are involved in a variety of functions, such as protein degradation (chaperones associated with proteosomes) or vesicular fusion (the N-ethylmaleimide-sensitive fusion protein, NSF) (May et al., 2001; Neuwald et al., 1999). The extended AAA+ family includes the clamp loader subunits, such as gamma, as well replication proteins such as the MCMs and cdc6 (Liu et al., 2000; May et al., 2001; Neuwald et al., 1999). The first structures for members of the AAA+ family were determined for delta-prime (Guenther et al., 1997) and for the D2 domain of NSF (Lenzen et al., 1998; Yu et al., 1998). Subsequently, the structures of several other AAA+ ATPases have been determined (for a recent review see (May et al., 2001)).

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The relationship between Delta-Prime and AAA+ proteins was first discovered on the basis of sequence comparisons by Andy Neuwald (Cold Spring Harbor Lab). The picture below compares the first two domains of Delta-prime, on the left, with that of NSF (on the right). The structure of NSF was determined simultaneously by Axel Brunger and Bill Weis.

The structure of the hexameric assembly formed by one of the domains of the AAA+ ATPase p97 is shown below.

Guenther, B. D., Onrust, R., Sali, A., O'Donnell, M., and Kuriyan, J. (1997). Crystal structure of the d' subunit of the clamp-loader complex of E. coli DNA polymerase III. Cell 91, 335-345.
Lenzen, C. U., Steinmann, D., Whiteheart, S. W., and Weis, W. I. (1998). Crystal structure of the hexamerization domain of N-ethylmaleimide- sensitive fusion protein. Cell 94, 525-536.
Liu, J., Smith, C. L., DeRyckere, D., DeAngelis, K., Martin, G. S., and Berger, J. M. (2000). Structure and function of Cdc6/Cdc18: implications for origin recognition and checkpoint control. Mol Cell 6, 637-648.
May, A. P., Whiteheart, S. W., and Weis, W. I. (2001). Unraveling the Mechanism of the Vesicle Transport ATPase NSF, the N- Ethylmaleimide-sensitive Factor. J Biol Chem 276, 21991-21994.
Neuwald, A. F., Aravind, L., Spouge, J. L., and Koonin, E. V. (1999). AAA+: A class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. Genome Res 9, 27-43.
Yu, R. C., Hanson, P. I., Jahn, R., and Brunger, A. T. (1998). Structure of the ATP-dependent oligomerization domain of N- ethylmaleimide sensitive factor complexed with ATP. Nat Struct Biol 5, 803-811.