title: Ca2+-dependent redox modulation of SERCA 2b by ERp57.
abstract: We demonstrated previously that calreticulin (CRT) interacts with the lumenal COOH-terminal sequence of sarco endoplasmic reticulum (ER) calcium ATPase (SERCA) 2b to inhibit Ca2+ oscillations. Work from other laboratories demonstrated that CRT also interacts with the ER oxidoreductase, ER protein 57 (also known as ER-60, GRP58; ERp57) during folding of nascent glycoproteins. In this paper, we demonstrate that ERp57 overexpression reduces the frequency of Ca2+ oscillations enhanced by SERCA 2b. In contrast, overexpression of SERCA 2b mutants defective in cysteines located in intralumenal loop 4 (L4) increase Ca2+ oscillation frequency. In vitro, we demonstrate a Ca2+-dependent and -specific interaction between ERp57 and L4. Interestingly, ERp57 does not affect the activity of SERCA 2a or SERCA 2b mutants lacking the CRT binding site. Overexpression of CRT domains that disrupt the interaction of CRT with ERp57 behave as dominant negatives in the Ca2+ oscillation assay. Our results suggest that ERp57 modulates the redox state of ER facing thiols in SERCA 2b in a Ca2+-dependent manner, providing dynamic control of ER Ca2+ homeostasis.
authors.affiliation: Dept. of Physiology, MSC 7756, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Patricia
authors.initials: P
authors.lastname: Camacho
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000648:ultrastructure; D007535:Isomerases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009865:Oocytes; D010084:Oxidation-Reduction; D019704:Protein Disulfide-Isomerases; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013438:Sulfhydryl Compounds / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D037282:Calreticulin; D006360:Heat-Shock Proteins; D020033:Protein Isoforms; D013438:Sulfhydryl Compounds; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D007535:Isomerases; C513196:PDIA3 protein, rat; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human; D000252:Calcium-Transporting ATPases; D003545:Cysteine; D002118:Calcium