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Nonassembled Human Chorionic Gonadotropin Subunits and -Homodimers Use Fast-Track Processing in the Secretory Pathway in Contrast to ß-Heterodimers

Heidelberg University Biochemistry Center (W.E.M., J.-M.K., J.R., V.S.), 69120 Heidelberg, Federal Republic of Germany; Institute for Biomedical Aging Research (P.B.), Austrian Academy of Sciences, Innsbruck A6020, Austria; and Hormone Biochemistry Laboratory, Institute of Self Organizing Systems and Biophysics (V.S.), North-Eastern Hill University, Permanent Campus, Shillong-793022, Meghalaya, India

Address all correspondence and requests for reprints to: Wolfgang E. Merz, Ph.D., Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Federal Republic of Germany. E-mail: wolfgang.merz{at}bzh.uni-heidelberg.de.

In multimeric glycoproteins, like glycoprotein hormones, mutual subunit interactions are required for correct folding, assembly, and transport in the secretory pathway. However, character and time course of these interactions need further elucidation. The influence of the glycoprotein hormone -subunit (GPH) on the folding of the human chorionic gonadotropin (hCG) ß-subunit (hCGß) in hCG ß-heterodimers was investigated in [³⁵S]Met/Cys-labeled JEG-3 cells. Completeness of disulfide bridge formation during the time course of folding was estimated by labeling with [³H]N-ethylmaleinimide of free thiol groups not yet consumed. Subunit association took place between immature hCGß (high ³H/³⁵S ratio) and almost completely folded GPH. Analysis revealed a highly dynamic maturation process comprising of at least eight main hCGß folding intermediates (molecular masses from 107 to 28 kDa) that could be micro-preparatively isolated and characterized. These hCGß variants developed while being associated with GPH. The 107-kDa variant was identified as a complex with calnexin. In contrast to hCG ß-heterodimers, free nonassociated hCGß, free large GPH, and GPH homodimers showed a fast-track-like processing in the secretory pathway. At 10 min before hCG secretion, sialylation of these variants had already been completed in the late Golgi, whereas hCG ß-heterodimers had still not arrived medial Golgi. This shows that the GPH in the hCG ß-heterodimers decelerates the maturation of the hCGß portion in the heterodimer complex. This results in a postponed approval of hCG ß-heterodimers by the endoplasmic reticulum quality control unlike GPH homodimers, free hCGß, and GPH subunits.