Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP. 3071 85

Hsp70 and Hsp90 chaperones are critical for protein quality control in the cytosol, whereas organelle-specific Hsp70/Hsp90 paralogs provide similar protection for mitochondria and the endoplasmic reticulum (ER). Cytosolic Hsp70/Hsp90 can operate sequentially with Hsp90 selectively associating with Hsp70 after Hsp70 is bound to a client protein. This observation has long suggested that Hsp90 could have a preference for interacting with clients at their later stages of folding. However, recent work has shown that cytosolic Hsp70/Hsp90 can directly interact even in the absence of a client, which opens up an alternative possibility that the ordered interactions of Hsp70/Hsp90 with clients could be a consequence of regulated changes in the direct interactions between Hsp70 and Hsp90. However, it is unknown how such regulation could occur mechanistically. Here, we find that the ER Hsp70/Hsp90 (BiP/Grp94) can form a direct complex in the absence of a client. Importantly, the direct interaction between BiP and Grp94 is nucleotide-specific, with BiP and Grp94 having higher affinity under ADP conditions and lower affinity under ATP conditions. We show that this nucleotide-specific association between BiP and Grp94 is largely due to the conformation of BiP. When BiP is in the ATP conformation its substrate-binding domain blocks Grp94; in contrast, Grp94 can readily associate with the ADP conformation of BiP, which represents the client-bound state of BiP. Our observations provide a mechanism for the sequential involvement of BiP and Grp94 in client folding where the conformation of BiP provides the signal for the subsequent recruitment of Grp94.
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PMID:The endoplasmic reticulum (ER) chaperones BiP and Grp94 selectively associate when BiP is in the ADP conformation. 3078 3

BiP is a major endoplasmic reticulum (ER) chaperone and is suggested to act as primary sensor in the activation of the unfolded protein response (UPR). How BiP operates as a molecular chaperone and as an ER stress sensor is unknown. Here, by reconstituting components of human UPR, ER stress and BiP chaperone systems, we discover that the interaction of BiP with the luminal domains of UPR proteins IRE1 and PERK switch BiP from its chaperone cycle into an ER stress sensor cycle by preventing the binding of its co-chaperones, with loss of ATPase stimulation. Furthermore, misfolded protein-dependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data elucidate a previously unidentified mechanistic cycle of BiP function that explains its ability to act as an Hsp70 chaperone and ER stress sensor.
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PMID:UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. 3169 87

The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and as an intracellular calcium storage compartment, facilitating calcium release-dependent cellular processes. ER calcium depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in ER calcium impact organellar proteostasis. Here we report that calcium selectively affects the dynamics of the abundant metazoan ER Hsp70 chaperone BiP, by enhancing its affinity for ADP. In the calcium-replete ER, ADP rebinding to post-ATP hydrolysis BiP-substrate complexes competes with ATP binding during both spontaneous and co-chaperone-assisted nucleotide exchange, favouring substrate retention. Conversely, in the calcium-depleted ER, relative acceleration of ADP-to-ATP exchange favours substrate release. These findings explain the rapid dissociation of certain substrates from BiP observed in the calcium-depleted ER and suggest a mechanism for tuning ER quality control and coupling UPR activity to signals that mobilise ER calcium in secretory cells.
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PMID:Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes. 3329 73


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