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MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

Yahui Yan1, Claudia Rato1, Lukas Rohland1,2

  • 1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.

Nature Communications
|February 3, 2019
PubMed

Insights

Mesencephalic astrocyte-derived neurotrophic factor (MANF) stabilizes protein folding by inhibiting the Hsp70 chaperone BiP. This interaction prevents BiP from releasing clients, aiding endoplasmic reticulum homeostasis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Neuroscience

Background:

  • Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotectant.
  • MANF is largely retained within the endoplasmic reticulum (ER) of producer cells.
  • MANF interacts with the ER-localized Hsp70 chaperone BiP to maintain protein folding homeostasis.

Purpose of the Study:

  • To elucidate the mechanism by which MANF interacts with BiP.
  • To investigate MANF's role in regulating BiP activity and client release.

Main Methods:

  • X-ray crystallography to determine the structure of the MANF SAP domain bound to BiP.
  • Biochemical assays to measure ADP release and ATP binding to BiP.
  • Cellular assays to assess ER stress responses in MANF-deficient cells.

Main Results:

  • The SAP domain of MANF selectively binds to the nucleotide-binding domain (NBD) of ADP-bound BiP.
  • MANF stabilizes the ADP-bound conformation of BiP by interacting with specific NBD subdomains.
  • MANF inhibits ADP release from and ATP binding to BiP, thereby preventing client protein release.
  • MANF-deficient cells exhibit reduced formation of ER stress-induced BiP-containing high molecular weight complexes.

Conclusions:

  • MANF functions as a nucleotide exchange inhibitor for BiP.
  • MANF stabilizes BiP-client complexes, contributing to protein folding homeostasis in the ER.
  • MANF's interaction with BiP is crucial for managing ER stress responses.

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