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. 2017 Oct 24;6:e29428. doi: 10.7554/eLife.29428

Figure 7. Hypothesized mechanisms by which AMPylation inactivates BiP.

Figure 7.

(A) ADP-bound unmodified BiP is strongly biased towards a domain-undocked conformation with low substrate ‘off’ rates. AMPylation (BiP-AMP) biases the ADP-bound chaperone towards a more domain-docked state with higher substrate ‘off’ rates. As a consequence, AMPylation enfeebles BiP-client interactions. (B) The contacts formed between the docked nucleotide binding domain (NBD) and substrate binding domain (SBD) of ATP-bound BiP are proposed to inhibit its basal ATPase activity (red arrow). J-domain interaction with BiP likely weakens these inhibitory interdomain contacts favoring ATP hydrolysis (Kityk et al., 2015) and triggering complete domain undocking, exposure of the interdomain linker (green), and stable substrate binding (red). By an allosteric mechanism, AMPylation on threonine 518 further strengthens the domain-docked conformation of ATP-bound BiP, which also strengthens the ATPase-inhibitory interdomain contacts (bold red arrow). This elevates the threshold for J domain-mediated stimulation of ATPase activity.