6h9u

From Proteopedia

Crystal structure of the BiP NBD and MANF SAP complex

Structural highlights

6h9u is a 2 chain structure with sequence from Cricetulus griseus and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.57Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MANF_MOUSE Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain. Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra. Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons. Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death. Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions. Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia. Following secretion by the ER/SR, directly binds to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells. Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions.[UniProtKB:P0C5H9][UniProtKB:P55145]

Publication Abstract from PubMed

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.

MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP.,Yan Y, Rato C, Rohland L, Preissler S, Ron D Nat Commun. 2019 Feb 1;10(1):541. doi: 10.1038/s41467-019-08450-4. PMID:30710085^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yan Y, Rato C, Rohland L, Preissler S, Ron D. 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. PMID:30710085 doi:http://dx.doi.org/10.1038/s41467-019-08450-4