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AMPylation targets the rate-limiting step of BiP’s ATPase cycle for its functional inactivation

DOI: 10.7554/eLife.29428 DOI Help

Authors: Steffen Preissler (University of Cambridge) , Lukas Rohland (University of Cambridge) , Yahui Yan (University of Cambridge) , Ruming Chen (University of Cambridge) , Randy J. Read (University of Cambridge) , David Ron (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 6

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 15916 , 11235

Open Access Open Access

Abstract: The endoplasmic reticulum (ER)-localized Hsp70 chaperone BiP contributes to protein folding homeostasis by engaging unfolded client proteins in a process that is tightly coupled to ATP binding and hydrolysis. The inverse correlation between BiP AMPylation and the burden of unfolded ER proteins suggests a post-translational mechanism for adjusting BiP’s activity to changing levels of ER stress, but the underlying molecular details are unexplored. We present biochemical and crystallographic studies indicating that irrespective of the identity of the bound nucleotide AMPylation biases BiP towards a conformation normally attained by the ATP-bound chaperone. AMPylation does not affect the interaction between BiP and J-protein co-factors but appears to allosterically impair J protein-stimulated ATP-hydrolysis, resulting in the inability of modified BiP to attain high affinity for its substrates. These findings suggest a molecular mechanism by which AMPylation serves as a switch to inactivate BiP, limiting its interactions with substrates whilst conserving ATP.

Subject Areas: Biology and Bio-materials

Beamlines: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography