title: Repeat motif-containing regions within thyroglobulin.
abstract: Thyroglobulin (precursor for thyroid hormone synthesis) is a large secreted glycoprotein comprising contiguous region I (multiple type-1 repeating units engaging the first ∼1,191 residues, followed by a ∼245-residue hinge region), regions II-III (multiple type-2 and 3 repeating units, comprising ∼720 residues), and the C-terminal cholinesterase-like (ChEL) domain (∼570 residues). A signal peptide attached to ChEL makes an independent secretory protein that binds to I-II-III, stabilizing it and rescuing the secretion of I-II-III that would otherwise be trapped in the endoplasmic reticulum (ER). In this study, we found that a signal peptide attached to regions II-III also makes for an efficient secretory protein that neither demonstrably interacts nor has its secretion enhanced by the presence of secretory ChEL. By contrast, region I, either with or without the hinge region, cannot be secreted on its own and remains in the ER where it is bound to ER chaperones BiP and GRP94. Whereas ChEL can rescue secretion of I-II-III, it can rescue I-II only very weakly, and region I not at all. Yet, ChEL begins to rescue region I in cells that also co-express secretory II-III. The data suggest that conformational maturation of region I is a limiting step in the thyroglobulin maturation process, and this step is facilitated by the presence of both regions II-III and ChEL. Mutations causing hypothyroidism might induce solely local/regional misfolding or may interfere more globally by impeding interactions between regions that are required for thyroglobulin secretion.
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, the University of Michigan Medical Center, Ann Arbor, Michigan 48109-0678, USA.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D020816:Amino Acid Motifs; D000091342:Endoplasmic Reticulum Chaperone BiP; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013954:Thyroglobulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; C053387:endoplasmin; D013954:Thyroglobulin