MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

Yahui Yan, Claudia Rato, Lukas Rohland, Steffen Preissler () and David Ron ()
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Yahui Yan: University of Cambridge
Claudia Rato: University of Cambridge
Lukas Rohland: University of Cambridge
Steffen Preissler: University of Cambridge
David Ron: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08450-4

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