1. Mechanistic model for the control of N‐domain movement and implication for IBMPFD. Schematic diagram for the control of the N‐domain conformation in (A) the wild‐type and (B) IBMPFD mutant p97 N–D1 fragment.
Mechanistic model for the control of N‐domain movement and implication for IBMPFD. Schematic diagram for the control of the N‐domain conformation in (A) the wild‐type and (B) IBMPFD mutant p97 N–D1 fragment. The N‐, D1‐, and D2‐domains are in magenta, blue, and green, respectively, and as labelled. The small yellow circles between N‐ and D1‐domains represent positions of mutations. Four states are defined for each nucleotide‐binding site in D1: Empty state, ATP state, ADP‐locked, and ADP‐open, as labelled. Each protomer is assumed to operate independently. The stimuli for changes in D1 nucleotide state may come either from the N‐domain or from ATP hydrolysis of the D2‐domain. In the ADP‐locked state, the N‐domains are in Down‐conformation with a pre‐bound ADP shown as a black rectangle. This ADP‐locked state has been observed crystallographically in wild‐type p97. In the ATP state, the N‐domains of hexameric wild‐type p97 could be either in an Up‐conformation with bound ATP shown as a black diamond or in a Down‐conformation in an ADP‐locked state, whereas the N‐domains of mutants adopt only the Up‐conformation as observed in this study. On the basis of available structural and biochemical information, we introduce two additional conformational states. The Empty state has the N‐domain conformation undefined and the nucleotide‐binding site shown as a black circle. The ADP‐open state also has an N‐domain conformation similar to that of Down‐conformation as determined by the crystal structure of R155H mutant with bound ADP, which is also shown as a black rectangle. Bound ADP can only be exchanged through the ADP‐open state. In wild‐type p97, the equilibration between ADP‐open and ADP‐locked favours heavily the latter and is presumably regulated by effectors such as p47 or ATP hydrolysis in D2‐domain. In IBMPFD mutants, the tight control between ADP‐open and ADP‐locked is disrupted and the equilibration is now favouring the ADP‐open state.
Wai Kwan Tang et al. EMBO J. 2010;29:
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