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)

Oligomeric proteins usually have to assemble into their final quartenary structure to be secreted. However, most immunoglobulin (Ig) light (L) chains can be exported as free chains, whereas only a few Ig L chains, here referred to as export-incompetent, have to assemble with Ig heavy (H) chains into antibody molecules to be secreted. In the absence of Ig H chain expression, these export-incompetent Ig L chains remain bound to BiP as partially folded monomers with only one of the two internal disulfide bonds being formed. To understand the apparent discrepancy in Ig L chain export, we performed assembly studies with chimeric Ig chains and found that the variable (V) domain of the export-incompetent NS1 kappa chain cannot mediate homodimer formation. Conversely, the V domain of the export-competent J558L lambda1 chain supports homodimer formation and, concordantly, these Ig L chains are secreted as noncovalently or covalently linked homodimers. We show that the export-incompetent mutant lambda1 FS62 chain forms disulfide bonds in both domains only upon pairing with Ig H chain and is secreted as part of an antibody. Therefore, Ig L chain assembly seems to be a prerequisite for complete folding, indicating that Ig L chain secretion generally depends on either homo- or heterodimer formation. We discuss a mechanism that controls oligomerization by monitoring the conformation of individual subunits that cannot proceed in folding prior to successful assembly.
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PMID:Assembly of immunoglobulin light chains as a prerequisite for secretion. A model for oligomerization-dependent subunit folding. 900 64

Not much is known about the features that determine the biological stability of a molecule retained in the endoplasmic reticulum (ER). Ig light (L) chains that are not secreted in the absence of Ig heavy (H) chain expression bind to the ER chaperone BiP as partially folded molecules until they are degraded. Although all Ig L chains have the same three-dimensional structure when part of an antibody molecule, the degradation rate of unassembled Ig L chains is not identical. For instance, the two nonsecreted murine Ig L chains, kappaNS1 and lambdaFS62, are degraded with half-lives of approximately 1 and 4 hr, respectively, in the same NS1 myeloma cells. Furthermore, the BiP/lambdaFS62 Ig L chain complex appears to be more stable than the BiP/kappaNS1 complex. Here, we used the ability of single Ig domains to form an internal disulfide bond after folding as a measure of the folding state of kappaNS1 and lambdaFS62 Ig L chains. Both of these nonsecreted L chains lack the internal disulfide bond in the variable (V) domain, whereas the constant (C) domain was folded in that respect. In both cases the unfolded V domain provided the BiP binding site. The stability of BiP binding to these two nonsecreted proteins was quite different, and both the stability of the BiP:Ig L chain complex and the half-life of the Ig L chain could be transferred from one Ig L chain isotype to the other by swapping the V domains. Our data suggest that the physical stability of BiP association with an unfolded region of a given light chain determines the half-life of that light chain, indicating a direct link between chaperone interaction and delivery of partially folded substrates to the mammalian degradation machinery.
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PMID:The variable domain of nonassembled Ig light chains determines both their half-life and binding to the chaperone BiP. 946 57

Unassembled immunoglobulin light chains expressed by the mouse plasmacytoma cell line NS1 (kappa(NS1)) are degraded in vivo with a half-life of 50-60 min in a way that closely resembles endoplasmic reticulum (ER)-associated degradation (). Here we show that the peptide aldehydes MG132 and PS1 and the specific proteasome inhibitor lactacystin effectively increased the half-life of kappa(NS1), arguing for a proteasome-mediated degradation pathway. Subcellular fractionation and protease protection assays have indicated an ER localization of kappa(NS1) upon proteasome inhibition. This was independently confirmed by the analysis of the folding state of kappa(NS1) and size fractionation experiments showing that the immunoglobulin light chain remained bound to the ER chaperone BiP when the activity of the proteasome was blocked. Moreover, kinetic studies performed in lactacystin-treated cells revealed a time-dependent increase in the physical stability of the BiP-kappa(NS1) complex, suggesting that additional proteins are present in the older complex. Together, our data support a model for ER-associated degradation in which both the release of a soluble nonglycosylated protein from BiP and its retrotranslocation out of the ER are tightly coupled with proteasome activity.
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PMID:Dissociation from BiP and retrotranslocation of unassembled immunoglobulin light chains are tightly coupled to proteasome activity. 1063 3