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

Prolyl 4-hydroxylase (P4-H) catalyses a vital post-translational modification in the biosynthesis of collagen. The enzyme consists of two distinct polypeptides forming an alpha 2 beta 2 tetramer (alpha = 64 kDa, beta = 60 kDa), the beta-subunit being identical to the multifunctional enzyme protein disulfide isomerase (PDI). By studying the cell-free synthesis of the rat alpha-subunit of P4-H we have shown that the alpha-subunit can be translocated, glycosylated and the signal peptide cleaved by dog pancreatic microsomal membranes to yield both singly and doubly glycosylated forms. When translations were carried out under conditions which prevent disulfide bond formation, the product synthesized formed aggregates which were associated with the immunoglobulin heavy chain binding protein (BiP). Translations carried out under conditions that promote disulfide bond formation yielded a product that was not associated with BiP but formed a complex with the endogenous beta-subunit (PDI). Complex formation was detected by co-precipitation of the newly synthesized alpha-subunit with antibodies raised against PDI, by sucrose gradient centrifugation and by chemical cross-linking. When microsomal vesicles were depleted of PDI, BiP and other soluble endoplasmic reticulum proteins, no complex formation was observed and the alpha-subunit aggregated even under conditions that promote disulfide bond formation. We have therefore demonstrated that the enzyme P4-H can be assembled at synthesis in a cell-free system and that the solubility of the alpha-subunit is dependent upon its association with PDI.
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PMID:Cell-free synthesis and assembly of prolyl 4-hydroxylase: the role of the beta-subunit (PDI) in preventing misfolding and aggregation of the alpha-subunit. 838 7

Phylogenetic analyses indicated that a series of paralogous gene pairs, found in two extensive regions on human chromosomal bands 6p21.3 and 9q33-34, were created by at least two independent duplications. The duplicated genes on chromosomal band 6p21.3 include the genes for type 11 collagen alpha2 subunit (COL11A2), NOTCH4 (mouse int-3 homologue), 70 kDa heat shock protein (HSPA1A, HSPA1B, and HSPA1L), valyl-tRNA synthetase 2 (VARS2), complement components (C2 and C4), pre-B cell leukemia transcription factor 2 (PBX2), retinoid X receptor beta (RXRB), NAT/RING3, and four other proteins. Their paralogous genes on chromosomal band 9q33-34 are genes for type 5 collagen alpha1 subunit (COL5A1), NOTCH1, 78 kDa glucose-regulated protein (HSPA5), valyl-tRNA synthetase 1 (VARS1), complement component V (C5), PBX3, retinoid X receptor alpha (RXRA), ORFX/RING3L, and others. Among these, the genes for collagen, complement components, NAT/RING3, PBX, and RXR appear to have been duplicated around the time of vertebrate emergence, supporting the idea that they were duplicated simultaneously at that time. Another group of genes that includes NOTCH and HSP appear to have diverged long before that time. A comparison of the physical maps of these two regions revealed that the genes which duplicated in the same period were arranged in almost the same order in the two regions, with the assumption of a few chromosomal rearrangements. We propose a possible model for the evolution of these regions, taking into account the molecular mechanisms of regional duplication, gene duplication, translocation, and inversion. We also propose that a comparative mapping of paralogous genes within the human genome would be useful for identifying new genes.
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PMID:Evolutionary significance of intra-genome duplications on human chromosomes. 946 76

Rheumatoid arthritis (RA) is the most common, crippling human autoimmune disease. Using Western blotting and tandem mass spectroscopy, we have identified the endoplasmic reticulum chaperone BiP, a 78-kDa glucose-regulated protein, as a possible autoantigen. It preferentially stimulated increased proliferation of synovial T cells from patients with RA but not from patients with other arthritides. Mice with established collagen- or pristane-induced arthritis developed IgG Abs to BiP. Although BiP injected in CFA failed to induce arthritis in several strains of rats and mice, including HLA-DR4(+/-)- and HLA-DR1(+/+)-transgenic animals, it completely inhibited the development of arthritis when given i.v. 1 wk before the injection of type II collagen arthritis. Preimmunization with BiP suppressed the development of adjuvant arthritis in Lewis rats in a similar manner. This is the first report of a mammalian chaperone that is an autoantigen in human RA and in experimental arthritis and that can also prevent the induction of experimental arthritis. These findings may stimulate the development of new immunotherapies for the treatment of RA.
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PMID:The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis. 1116 Jan 88

Autoreactivity plays a major role in the pathogenesis of RA. The rheumatoid factor has been and still is for now more than 50 years the only autoreactivity that is clinically applied in the diagnosis of RA. This well reflects the current way of thinking that a single antigen or a single cause drives an individual into disease. Although by now many other autoantigens and autoreactivities have been described, their discovery was always on the search for the one and only autoreactivity that causes RA. This includes also immune reactivities directed against xenogenic antigens. But, none of the known RA-associated autoreactivities is present in all RA patients and none of them occurs exclusively in RA. Thus, the observed sensitivities and specificities are well below 100%. Therefore, RA has often been postulated to consist of various immunological subentities with similar clinical symptoms. Nevertheless, none of the autoreactivities correlates with a distinct clinical feature or course of disease. It is about time to say good-bye to the idea that a single antigen or immunoreactvity causes and maintains rheumatoid arthritis. In this paper we present RA as the clinical outcome of an immune system that has shifted from a healthy to an autoimmune steady state. This is accomplished by many different reactivities and autoreactivities that occur either in parallel or one after the other. The entirety of the known RA-associated reactivities and (auto)antigens is presented in detail. The major RA-relevant autoantigens comprise BiP, citrulline, the Sa-antigen, hnRNP A2, p205, IgG, calpastatin, calreticulin, collagen and the shared HLA-DR epitope. The accumulation of factor--involving autoreactivities, cytokines, environmental and genetic factors--that challenge the normal regulatory mechanisms of the immune system lead to a regulatory catastrophe. In individuals developing the clinical features of RA the immune system has been regulated to a new--autoimmune--steady state. This attractor "rheumatoid arthritis" has many features of what has originally been described by Irun Cohen as the immunological homunculus: The healthy immune system is configured such as to direct its attention to major self-antigens. Thus it creates an autoreactivity to many autoantigens as a prerequisite for regulatory mechanisms that are sufficient to control them. The shift from the normal to rheumatoid attractor involves the inflammatory cytokines TNF-alpha, IL-1 and IL-6, autoreactive T- and B cells directed at a variety of synovial and systemic antigens, activated dendritic cells and macrophages, tissue destruction and genetic factors such as the association with shared epitope. Environmental factors involved may also, but do not necessarily, include infection. With the appearance of clinical features of RA, naive, potentially autoreactive T cells infiltrate the synovial compartment and become activated by dendritic cells and other APCs. The autoantigenic peptides that are presented to these T cells are derived from inflammatory cell and tissue destruction as well as from tissue repair and remodeling processes. These T cells proliferate and either provide help to B cells with the specificity to the same antigens or cause direct cytopathic tissue damage. Thereby, more and novel antigens are generated, released and presented again to naive or primed autoreactive T cells. These processes involving cytokines, tissue destruction and autoreactive T cells are sufficient to maintain RA even without the permanent presence of a triggering agent. The recursive autoimmune processes are well consistent with the finding of the many different autoreactivities in RA and their respective sensitivities and specificities. The massive influx of T cells into the arthritic joint is accompanied by the anergization of over 90% of T cells in this compartment--which further substantiates the concept of the RA attractor within the self-regulating immune system. Thereby, the RA-attracted immune system is not able to completely downregulate the inflammation and the local tissue damage/repair. Thus, the immune system is permanently stimulated and suddenly by chance shifts to a stable state different from the healthy system--reaching the wide fields of rheumatoid arthritis which in itself is self-sustaining as the healthy state before disease onset.
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PMID:[The immunologic homunculus in rheumatoid arthritis. A new viewpoint of immunopathogenesis in rheumatoid arthritis and therapeutic consequences]. 1126 10

Cartilage oligomeric matrix protein (COMP), a large pentameric glycoprotein and member of the thrombospondin (TSP) group of extracellular proteins, is found in the territorial matrix surrounding chondrocytes. More than 50 unique COMP mutations have been identified as causing two skeletal dysplasias: pseudoachondroplasia (PSACH); and multiple epiphyseal dysplasia (EDM1). Recent studies suggest that calcium-binding and calcium-induced protein folding differ between wild type and mutant proteins, and abnormal processing of the mutant COMP protein contributes to the characteristic enlarged lamellar appearing rER cisternae in PSACH and EDMI chondrocytes in vivo and in vitro. Towards the goal of delineating the pathogenesis of PSACH and EDM1, in-vivo PSACH growth plate and in-vitro PSACH chondrocytes cultured in alginate beads were examined to identify and localize the chaperone proteins participating in the processing of the retained extracellular matrix proteins in the PSACH rER. Aggrecan was localized to both the rER cisternae and matrix while COMP and type IX collagen were only found in the rER. Type II collagen was solely found in the ECM suggesting that it is processed and transported differently from other retained ECM proteins. Five chaperone proteins: BiP (Grp78); calreticulin (CRT); protein disulfide (PDI); ERp72; and Grp94, demonstrated immunoreactivity in the enlarged PSACH cisternae and the short rER channels of chondrocytes from both in-vivo and in-vitro samples. The chaperone proteins cluster around the electron dense material within the enlarged rER cisternae. CRT, PDI and GRP94 AB-gold particles appear to be closely associated with COMP. Immunoprecipitation and Western blot, and Fluorescence Resonance Energy Transfer (FRET) analyses indicate that CRT, PDI and GRP94 are in close proximity to normal and mutant COMP and BiP to mutant COMP. These results suggest that these proteins play a role in the processing and transport of wild type COMP in normal chondrocytes and in the retention of mutant COMP in PSACH chondrocytes.
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PMID:Calreticulin, PDI, Grp94 and BiP chaperone proteins are associated with retained COMP in pseudoachondroplasia chondrocytes. 1147 Apr 1

Rheumatoid arthritis (RA) is a major systemic autoimmune disease. A plethora of putative autoantigens has been described by the reactivity of antibodies present in the sera of patients. Despite this there is little evidence implicating most of them in its pathogenesis. Autoantigens fall into two major groups: first, those that are associated with the joint, such as collagen type II, human chondrocyte glycoprotein 39, and proteoglycans, for which a pathogenic role is easily understood; and second, those proteins not associated with the joint. Of these there are three groups: (1) highly conserved foreign antigens with human homologues, such as heat shock proteins (HSPs), in which the initiating antigenic stimulus may be through infection; (2) post-translationally altered proteins, such as citrullinated filaggrin, to which autoantibodies show high specificity but low sensitivity for RA and immunoglobulin G; and (3) ubiquitous proteins, such as glucose-6-phosphate isomerase, p205, and HSPs secreted during stress, such as BiP. The mechanisms by which such ubiquitous antigens cause pathology predominantly in the joints are difficult to understand. Autoantibodies, such as rheumatoid factors, that form immune complexes resulting in activation of phagocytic cells or the complement system, may cause joint pathology by deposition in the joints. Such an explanation, however, is not available for all of these autoantigens. It is possible that pathology may be the outcome of disturbed immunoregulation.
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PMID:Autoantigens and immune pathways in rheumatoid arthritis. 1267 29

Collagen X is a short chain collagen expressed specifically by the hypertrophic chondrocytes of the cartilage growth plate during endochondral bone formation. Accordingly, COL10A1 mutations disrupt growth plate function and cause Schmid metaphyseal chondrodysplasia (SMCD). SMCD mutations are almost exclusively located in the NC1 domain, which is crucial for both trimer formation and extracellular assembly. Several mutations are expected to reduce the level of functional collagen X due to NC1 domain misfolding or exclusion from stable trimer formation. However, other mutations may be tolerated within the structure of the assembled NC1 trimer, allowing mutant chains to exert a dominant-negative impact within the extracellular matrix. To address this, we engineered SMCD mutations that are predicted either to prohibit subunit folding and assembly (NC1del10 and Y598D, respectively) or to allow trimerization (N617K and G618V) and transfected these constructs into 293-EBNA and SaOS-2 cells. Although expected to form stable trimers, G618V and N617K chains (like Y598D and NC1del10 chains) were secreted very poorly compared with wild-type collagen X. Interestingly, all mutations resulted in formation of an unusual SDS-stable dimer, which dissociated upon reduction. As the NC1 domain sulfhydryl group is not solvent-exposed in the correctly folded NC1 monomer, disulfide bond formation would result only from a dramatic conformational change. In cells expressing mutant collagen X, we detected significantly increased amounts of the spliced form of X-box DNA-binding protein mRNA and up-regulation of BiP, two key markers for the unfolded protein response. Our data provide the first clear evidence for misfolding of SMCD collagen X mutants, and we propose that solvent exposure of the NC1 thiol may trigger the recognition and degradation of mutant collagen X chains.
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PMID:Misfolding of collagen X chains harboring Schmid metaphyseal chondrodysplasia mutations results in aberrant disulfide bond formation, intracellular retention, and activation of the unfolded protein response. 1569 17

HSP47 is an endoplasmic reticulum (ER)-resident molecular chaperone involved in collagen production. This study examined the stress-induced pattern of hsp47 gene expression in Xenopus cultured cells and embryos. Sequence analysis revealed that protein encoded by the hsp47 cDNA exhibited 70-77% identity with fish, avian and mammalian HSP47. In A6 kidney epithelial cells hsp47 mRNA and HSP47 were present constitutively and inducible by heat shock but not ER stressors including tunicamycin and A23187, both of which enhanced BiP mRNA. Furthermore A23187 treatment inhibited constitutive accumulation of hsp47 mRNA and retarded heat-induced accumulation of hsp47 and hsp70 mRNA. Interestingly, hsp47 gene expression but not hsp70 or BiP mRNA accumulation was enhanced by treatment with a procollagen-specific stressor, beta-aminopropionitrile. In Xenopus embryos hsp47 mRNA was present constitutively throughout development. In tailbud embryos hsp47 mRNA was enriched in tissues associated with collagen production including notochord, somites and head region. Heat shock-induced accumulation of hsp47 mRNA was enhanced primarily in embryonic tissues already exhibiting hsp47 mRNA accumulation. These studies suggest that the pattern of Xenopus hsp47 gene expression is similar to hsp70 in response to heat shock but also displays unique features including a response to a procollagen-specific stressor and preferential expression in collagen-containing tissues.
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PMID:Examination of the stress-induced expression of the collagen binding heat shock protein, hsp47, in Xenopus laevis cultured cells and embryos. 1638 21


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