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J Biol Chem, Vol. 274, Issue 1, 101-107, January 1, 1999

Sequential Cleavage and Excision of a Segment of the Thyrotropin Receptor Ectodomain

Simon de BernardDagger , Micheline MisrahiDagger , Jean-Claude Huet§, Isabelle BeauDagger , Agnès DesrochesDagger , Hugues LoosfeltDagger , Christophe PichonDagger , Jean-Claude Pernollet§, and Edwin MilgromDagger

From Dagger  the Unité de Recherches Hormones et Reproduction, INSERM, Unité 135, Hôpital de Bicêtre, 94275 Le Kremlin Bicêtre, France and § Biochimie et Structure des Protéines, INRA, Unité 377, 78352 Jouy-en-Josas, France

The thyrotropin (TSH) receptor belongs to a subfamily of G protein-coupled receptors, which also includes luteinizing hormone and follicle-stimulating hormone receptors. The TSH receptor (TSHR) differs from the latter by the presence of an additional specific segment in the C-terminal part of its ectodomain. We show here that this insertion is excised in the majority of receptor molecules. Preparation of specific monoclonal antibodies to this region, microsequencing, enzyme-linked immunosorbent assay, and immunoblot studies have provided insight into the mechanisms of this excision. In the human thyroid gland, N termini of the transmembrane receptor beta  subunit were found to be phenylalanine 366 and leucines 370 and 378. In transfected L cells a variety of other more proximal N termini were found, probably corresponding to incomplete excisions. The most extreme N terminus was observed to lie at Ser-314. These observations suggest that after initial cleavage at Ser-314 the inserted fragment of TSHR is progressively clipped out by a series of cleavage reactions progressing up to amino acids 366-378. The impossibility of recovering the excised fragment from purified receptor, cell membranes, or culture medium supports this interpretation. The cleavage enzyme has previously been shown to be inhibited by BB-2116, an inhibitor of matrix metalloproteases. However, we show here that it is unaffected by tissue inhibitors of metalloproteases. The cleavage enzyme is very similar to TACE (tumor necrosis factor alpha -converting enzyme) in both these characteristics. However, incubation of the TSH receptor with the purified recombinant catalytic domain of TACE, co-transfection of cells with TACE and TSHR expression vectors, and the use of mutated Chinese hamster ovary cells in which TACE is inactive suggested that the TSHR cleavage enzyme is different from TACE. TACE and TSHR cleavage enzyme may thus possibly be related but different members of the adamalysin family of metzincin metalloproteases.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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