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)

The present study was undertaken to identify and characterize molecular chaperones that assist in the folding of apolipoprotein (apo) B, a secretory protein that requires assembly with lipids (lipidation) for its secretion. Both HepG2 cells, normally secreting full-length apoB (apoB-100), and C127 cells transfected to secrete truncated forms of apoB, apoB-41, apoB-29, and apoB-17, respectively, were employed. C127 cells were used to determine whether chaperone binding is dependent on apoB lipidation as they secrete both unlipidated and lipidated apoB forms despite their lack of microsomal triglyceride transfer protein (MTP), which mediates lipidation of apoB in HepG2 cells. The endoplasmic reticulum (ER)-resident molecular chaperones GRP94, calreticulin, and ERp72 were co-immunoprecipitated with apoB-100 from HepG2 cell lysates following cross-linking of proteins in living cells. The same chaperones including BiP/GRP78 were also associated with all truncated forms of apoB. Sequential immunoprecipitation with antibodies to MTP and apoB revealed the presence of ternary complexes containing apoB-100, MTP, and ERp72. However, MTP is not obligatory for the binding of ERp72 as it was associated with all truncated forms of apoB in C127 cells that lack MTP. The interactions between apoB-100 and ERp72 or GRP94 persisted for at least 2 h following a 30-min pulse. Thus, BiP/GRP78, calreticulin, ERp72, and GRP94 may participate in critical steps in the folding of apoB before any substantial lipidation occurs. ERp72 and GRP94 may also mediate the folding of more advanced folding intermediates and/or target the misfolded underlipidated pool of apoB for degradation.
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PMID:Multiple molecular chaperones interact with apolipoprotein B during its maturation. The network of endoplasmic reticulum-resident chaperones (ERp72, GRP94, calreticulin, and BiP) interacts with apolipoprotein b regardless of its lipidation state. 969 98

Familial hypobetalipoproteinemia (FHBL) is associated with mutations in the APOB gene. We reported the first missense APOB mutation, R463W, in an FHBL kindred (Burnett, J. R., Shan, J., Miskie, B. A., Whitfield, A. J., Yuan, J., Tran, K., Mc-Knight, C. J., Hegele, R. A., and Yao, Z. (2003) J. Biol. Chem. 278, 13442-13452). Here we identified a second nonsynonymous APOB mutation, L343V, in another FHBL kindred. Heterozygotes for L343V (n = 10) had a mean plasma apoB at 0.31 g/liter as compared with 0.80 g/liter in unaffected family members (n = 22). The L343V mutation impaired secretion of apoB-100 and very low density lipoproteins. The secretion efficiency was 20% for B100wt and 10% for B100LV and B100RW. Decreased secretion of mutant apoB-100 was associated with increased endoplasmic reticulum retention and increased binding to microsomal triglyceride transfer protein and BiP. Reduced secretion efficiency was also observed with B48LV and B17LV. Biochemical and biophysical analyses of apoB domain constructs showed that L343V and R463W altered folding of the alpha-helical domain within the N terminus of apoB. Thus, proper folding of the alpha-helical domain of apoB-100 is essential for efficient secretion.
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PMID:Missense mutations in APOB within the betaalpha1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia. 1758 43