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MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP

Author

Listed:
  • Yahui Yan

    (University of Cambridge)

  • Claudia Rato

    (University of Cambridge)

  • Lukas Rohland

    (University of Cambridge
    Center for Molecular Biology (ZMBH) of Heidelberg University)

  • Steffen Preissler

    (University of Cambridge)

  • David Ron

    (University of Cambridge)

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.

Suggested Citation

  • Yahui Yan & Claudia Rato & Lukas Rohland & Steffen Preissler & David Ron, 2019. "MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08450-4
    DOI: 10.1038/s41467-019-08450-4
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    Cited by:

    1. Melissa A. Graewert & Maria Volkova & Klara Jonasson & Juha A. E. Määttä & Tobias Gräwert & Samara Mamidi & Natalia Kulesskaya & Johan Evenäs & Richard E. Johnsson & Dmitri Svergun & Arnab Bhattacharj, 2024. "Structural basis of CDNF interaction with the UPR regulator GRP78," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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