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Volume 272, Number 45, Issue of November 7, 1997 pp. 28296-28300
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

An N-Linked Glycosylation Motif from the Noncleaving Luteinizing Hormone Receptor Substituted for the Homologous Region (Gly³⁶⁷ to Glu³⁶⁹) of the Thyrotropin Receptor Prevents Cleavage at Its Second, Downstream Site

(Received for publication, June 9, 1997, and in revised form, August 22, 1997)

From the Thyroid Molecular Biology Unit, Veterans Administration Medical Center and the University of California, San Francisco, California 94121

The thyrotropin receptor (TSHR) exists in two forms (single polypeptide and two subunits), whereas the lutropin/chorionic gonadotropin receptor (LH/CGR) is a single chain. Recent data suggest that the TSHR cleaves at two sites. We mutagenized selected chimeric TSH-LH/CGR to localize the cleavage sites in the TSHR. All 23 receptors mutated in the estimated vicinity of the upstream site cleaved into two subunits as determined by ¹²⁵I-TSH cross-linking to intact cells. In contrast, in a series of mutations homologous to the noncleaving LH/CGR, the downstream TSHR cleavage site localized to three amino acids (GQE^367-369). Remarkably, group substitution of these residues, but not substitution of individual residues, abolished cleavage. Moreover, the mutation that prevented cleavage (GQE^367-369NET) transposed a motif (NET^291-293) that is glycosylated in the LH/CGR. TSHR cleavage or noncleavage after substitution of GQE^367-369 with other triplets (AAA, NQE, and NQT) was consistent with a role for N-linked glycosylation at this site.

In summary, our data (i) support the concept that the TSHR cleaves at two sites, (ii) relate TSHR residues GQE^367-369 to cleavage at the second, downstream site, and (iii) suggest that cleavage or noncleavage at site two is related to N-linked glycosylation. These findings provide new insight into the evolutionary divergence of two closely related receptors.

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