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MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

DOI: 10.1038/s41467-019-08450-4 DOI Help

Authors: Yahui Yan (Cambridge Institute for Medical Research, University of Cambridge) , Claudia Rato (Cambridge Institute for Medical Research, University of Cambridge) , Lukas Rohland (Cambridge Institute for Medical Research, University of Cambridge) , Steffen Preissler (Cambridge Institute for Medical Research, University of Cambridge) , David Ron (Cambridge Institute for Medical Research, University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: February 2019
Diamond Proposal Number(s): 15916

Open Access Open Access

Abstract: Despite its known role as a secreted neuroprotectant, much of the mesencephalic astrocyte-derived neurotrophic factor (MANF) is retained in the endoplasmic reticulum (ER) of producer cells. There, by unknown mechanisms, MANF plays a role in protein folding homeostasis in complex with the ER-localized Hsp70 chaperone BiP. Here we report that the SAF-A/B, Acinus, and PIAS (SAP) domain of MANF selectively associates with the nucleotide binding domain (NBD) of ADP-bound BiP. In crystal structures the SAP domain engages the cleft between NBD subdomains Ia and IIa, stabilizing the ADP-bound conformation and clashing with the interdomain linker that occupies this site in ATP-bound BiP. MANF inhibits both ADP release from BiP and ATP binding to BiP, and thereby client release. Cells lacking MANF have fewer ER stress-induced BiP-containing high molecular weight complexes. These findings suggest that MANF contributes to protein folding homeostasis as a nucleotide exchange inhibitor that stabilizes certain BiP-client complexes.

Journal Keywords: Chaperones; Endoplasmic reticulum; X-ray crystallography

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

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s41467-019-08450-4.pdf