RGD Reference Report - Folding of thyroglobulin in the calnexin/calreticulin pathway and its alteration by loss of Ca2+ from the endoplasmic reticulum. - Rat Genome Database

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Folding of thyroglobulin in the calnexin/calreticulin pathway and its alteration by loss of Ca2+ from the endoplasmic reticulum.

Authors: Di Jeso, B  Ulianich, L  Pacifico, F  Leonardi, A  Vito, P  Consiglio, E  Formisano, S  Arvan, P 
Citation: Di Jeso B, etal., Biochem J. 2003 Mar 1;370(Pt 2):449-58.
RGD ID: 7205668
Pubmed: PMID:12401114   (View Abstract at PubMed)
PMCID: PMC1223171   (View Article at PubMed Central)
DOI: DOI:10.1042/BJ20021257   (Journal Full-text)

During its initial folding in the endoplasmic reticulum (ER), newly synthesized thyroglobulin (Tg) is known to interact with calnexin and other ER molecular chaperones, but its interaction with calreticulin has not been examined previously. In the present study, we have investigated the interactions of endogenous Tg with calreticulin and with several other ER chaperones. We find that, in FRTL-5 and PC-Cl3 cells, calnexin and calreticulin interact with newly synthesized Tg in a carbohydrate-dependent manner, with largely overlapping kinetics that are concomitant with the maturation of Tg intrachain disulphide bonds, preceding Tg dimerization and exit from the ER. Calreticulin co-precipitates more newly synthesized Tg than does calnexin; however, using two different experimental approaches, calnexin and calreticulin were found in ternary complexes with Tg, making this the first endogenous protein reported in ternary complexes with calnexin and calreticulin in the ER of live cells. Depletion of Ca(2+) from the ER elicited by thapsigargin (a specific inhibitor of ER Ca(2+)-ATPases) results in retention of Tg in this organelle. Interestingly, thapsigargin treatment induces the premature exit of Tg from the calnexin/calreticulin cycle, while stabilizing and prolonging interactions of Tg with BiP (immunoglobulin heavy chain binding protein) and GRP94 (glucose-regulated protein 94), two chaperones whose binding is not carbohydrate-dependent. Our results suggest that calnexin and calreticulin, acting in ternary complexes with a large glycoprotein substrate such as Tg, might be engaged in the folding of distinct domains, and indicate that lumenal Ca(2+) strongly influences the folding of exportable glycoproteins, in part by regulating the balance of substrate binding to different molecular chaperone systems within the ER.

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein-containing complex  IDA 7205668; 7205668; 7205668 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
identical protein binding  IPITg (Rattus norvegicus)7205668homodimerizationRGD 
protein-containing complex binding  IPICanx (Rattus norvegicus) and Calr (Rattus norvegicus)7205668 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Calr  (calreticulin)
Canx  (calnexin)
Tg  (thyroglobulin)


Additional Information