MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

Nat Commun. 2019 Feb 1;10(1):541. doi: 10.1038/s41467-019-08450-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • CHO Cells
  • Chlorocebus aethiops
  • Cricetulus
  • Crystallography, X-Ray
  • Endoplasmic Reticulum / metabolism*
  • HEK293 Cells
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Models, Biological
  • Nerve Growth Factors / chemistry
  • Nerve Growth Factors / metabolism*
  • Nucleotides / metabolism*
  • Protein Binding
  • Protein Domains
  • Static Electricity
  • Unfolded Protein Response

Substances

  • Heat-Shock Proteins
  • MANF protein, mouse
  • Nerve Growth Factors
  • Nucleotides
  • Adenosine Triphosphate
  • molecular chaperone GRP78