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)

We have studied the folding, processing, and association with two endoplasmic reticulum (ER) resident proteins of the abnormal type I procollagen molecules produced by a strain of fibroblasts harboring a 4.5 kilobase deletion in an allele of COL1A2 (Willing, M. C., Cohn, D.H., Starman, B. Holbrook, K.A., Greenberg, C.R., and Byers, P.H. (1988) J. Biol. Chem. 263, 8398-8404). By sequencing cDNA, we found that the mutant allele encodes pro alpha 2(I) chains that are shortened by 180 amino acids but retain the Gly-X-Y repeat pattern crucial for collagen triple helix formation. The type I procollagen molecules that incorporated the shortened chain were retained intracellularly and were stable. The triple helical domain in these molecules did not attain a normal conformation and remained accessible to posttranslational modifying enzymes amino-terminal to the deletion site for a prolonged period. The abnormal molecules folded into a triple helical conformation more slowly than the normal molecules, and the amino-terminal ends of the pro alpha 1(I) chains failed to become protease-resistant. While the abnormal procollagen molecules were not bound by the ER-resident protein BiP, they stably associated with protein disulfide isomerase, the beta-subunit of prolyl-4-hydroxylase. These results indicate that some mutations in type I collagen genes both transiently delay folding and permanently disrupt the structure of the triple helix and suggest that binding to prolyl-4-hydroxylase helps to retain certain abnormal procollagen molecules within the ER.
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PMID:Defective folding and stable association with protein disulfide isomerase/prolyl hydroxylase of type I procollagen with a deletion in the pro alpha 2(I) chain that preserves the Gly-X-Y repeat pattern. 133 53

A heterozygous single base change in exon 49 of COL1A1, which converted the codon for pro alpha 1(I) carboxyl-terminal propeptide residue 94 from tryptophan (TGG) to cysteine (TGT) was identified in a baby with lethal osteogenesis imperfecta (OI64). The C-propeptide mutations in OI64 and in another lethal osteogenesis imperfecta cell strain (OI26), which has a frameshift mutation altering the sequence of the carboxyl-terminal half of the propeptide (Bateman, J. F., Lamande, S. R., Dahl, H.-H. M., Chan, D., Mascara, T. and Cole, W. G. (1989) J. Biol. Chem. 264, 10960-10964), disturbed procollagen folding and retarded the formation of disulfide-linked trimers. Although assembly was delayed, the presence of slowly migrating, overmodified alpha 1(I) and alpha 2(I) chains indicated that mutant pro alpha 1(I) could associate with normal pro alpha 1(I) and pro alpha 2(I) to form pepsin-resistant triple-helical molecules, a proportion of which were secreted. Further evidence of the aberrant folding of mutant procollagen in OI64 and OI26 was provided by experiments demonstrating that the endoplasmic reticulum resident molecular chaperone BiP, which binds to malfolded proteins, was specifically bound to type I procollagen and was coimmunoprecipitated in the osteogenesis imperfecta cells but not control cells. Experiments with brefeldin A, which inhibits protein export from the endoplasmic reticulum, demonstrated that unassembled mutant pro alpha 1(I) chains were selectively degraded within the endoplasmic reticulum resulting in reduced collagen production by the osteogenesis imperfecta cells. This biosynthetic deficiency was reflected in the inability of OI64 and OI26 cells to produce a substantial in vitro collagenous matrix when grown in the continuous presence of ascorbic acid to allow collagen matrix formation. Both these carboxyl-terminal propeptide mutants showed a marked reduction in collagen accumulation to 20% (or less) of control cultures, comparable to the reduced collagen content of tissues from OI26.
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PMID:Endoplasmic reticulum-mediated quality control of type I collagen production by cells from osteogenesis imperfecta patients with mutations in the pro alpha 1 (I) chain carboxyl-terminal propeptide which impair subunit assembly. 772 66

Hsp47, an endoplasmic reticulum resident protein, has gelatin-binding and procollagen-binding properties and has been hypothesized to function as a molecular chaperone in regulating procollagen folding and/or assembly. In this report, we further investigate the interaction of Hsp47 with polysome-associated alpha 1(I) procollagen chains following antisense treatment of 3T6 cells. For these studies, we employed phosphorothioate oligodeoxynucleotides directed to the first five codons of Hsp47 that straddle the predicted translation initiation site of mouse Hsp47. Cells depleted of Hsp47 in this manner were observed to produce diminished amounts of fully elongated nascent alpha 1(I) procollagen while accumulating shorter procollagen peptides associated with peptidyl-tRNA. Pulse-labeling of cells with [35S]methionine followed by treatment with puromycin and immunoprecipitation with anti-Hsp47 and anti-procollagen antibodies revealed that Hsp47 is associated with alpha 1(I) procollagen at a very early point during translocation of the nascent procollagen chains. Although Hsp47 appears to possess properties similar to grp78/BiP, Hsp47 binding early during translocation favors a more specialized specific function relative to chain selection or completion of stable folding in type I procollagen.
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PMID:Hsp47 and the translation-translocation machinery cooperate in the production of alpha 1(I) chains of type I procollagen. 790 76

Of 20 fibroblast cell strains from patients with osteogenesis imperfecta (OI), a disease caused by mutations in the genes encoding type I procollagen, three had increased synthesis of BiP (GRP78), an hsp70-related, endoplasmic reticulum-resident protein. All three strains carry unique mutations in pro alpha 1(I) chains which impair type I procollagen chain association. Immunoprecipitation and pulse-chase experiments show that BiP (immunoglobulin heavy chain-binding protein) stably binds pro alpha 1(I) chains in these three cell strains after a brief lag. Ascorbate, which increases procollagen synthesis, increases BiP synthesis and content in these three strains and not in the others. In one of these three strains, BiP content is constitutively elevated prior to ascorbate treatment, and BiP is less inducible. This strain also has relatively high levels of synthesis and content of GRP94, another endoplasmic reticulum-resident stress protein. Pretreating each of the three cell strains to increase their BiP content reduces subsequent ascorbate-mediated BiP induction. BiP synthesis in the 17 other OI strains examined, which had a variety of type I procollagen mutations, was normal. These results suggest that BiP is induced by and binds procollagen with specific types of mutations: ones in the carboxyl-terminal propeptide that interfere with chain association. The recognition by BiP of such procollagen in OI cell strains shows that BiP plays a role in the physiological response to the production of some disease-producing abnormal proteins.
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PMID:BiP binds type I procollagen pro alpha chains with mutations in the carboxyl-terminal propeptide synthesized by cells from patients with osteogenesis imperfecta. 834 98

Transcription of the gene encoding GRP78/BiP, a calcium-binding molecular chaperone localized in the endoplasmic reticulum, is induced in mammalian cells through gradual depletion of the intracellular calcium stores. The multimeric CCAAT binding factor, CBF/NF-Y, binds to the most proximal CCAAT regulatory element (C1) of the grp78 promoter required for both basal level expression and stress response. Using an in vitro transcription system, we show through factor competition and immunodepletion that the grp78 C1-mediated enhancement of transcription requires primarily CBF. Correlating with the previous observation that CBF binding to the 78C1 site is enhanced by EGTA and EDTA, these divalent cation chelators specifically stimulate 78C1-directed transcription. In contrast, increasing amounts of calcium ions are inhibitory. These results provide evidence that CBF is functionally important in transactivating the grp78 C1 transcriptional activity, and suggest a possible mechanism by which grp78 transcription is stimulated by calcium depletion. We further discovered that in addition to binding CBF, both the 78C1 element and the CBF binding site of the alpha2(I) collagen promoter interact weakly with the multifunctional transcription factor YY1. Our studies show that the binding sites for CBF and YY1 are distinct for the two promoter sites, suggesting that YY1 and other interacting factors could exert differential effects on individual promoters bearing the same CBF site.
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PMID:Calcium-sensitive transcriptional activation of the proximal CCAAT regulatory element of the grp78/BiP promoter by the human nuclear factor CBF/NF-Y. 891 May 50

Chronic liver injury, often caused by alcoholism and viral hepatitis, causes liver fibrosis via the induction of collagen production. In liver fibrosis, hepatic stellate cells (HSCs) are activated and transform into myofibroblasts, which actively produce and secrete collagen into the extracellular matrix. Hsp47 (heat shock protein 47) is a collagen-specific molecular chaperone that is essential for the maturation and secretion of collagen. Here, we used the Cre-LoxP system to disrupt the Hsp47 gene in isolated HSCs from Hsp47 floxed mice. Immature type I procollagen accumulated and partially aggregated in Hsp47-KO HSCs. This accumulation was augmented when autophagy was inhibited, which induced expression of the endoplasmic reticulum (ER) stress-inducible proteins BiP (immunoglobulin heavy chain-binding protein) and Grp94 (94-kDa glucose-regulated protein). The inhibition of autophagy in Hsp47-KO HSCs also induced CHOP (CCAAT/enhancer-binding protein homologous protein), which is an ER stress-induced transcription factor responsible for apoptosis. These data suggest that apoptosis is induced through ER stress by procollagen accumulation in Hsp47-KO HSCs when autophagy is inhibited. Thus, Hsp47 could be a promising therapeutic target in liver fibrosis.
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PMID:Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. 2552 67