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Autoimmune Disease Unit, Cedars-Sinai Research Institute and School of Medicine, University of California, Los Angeles, California 90048
Address all correspondence and requests for reprints to: Basil Rapoport, M.B., Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048. E-mail: rapaportB{at}cshs.org
Some TSH receptors (TSHR) on the cell surface cleave into A and B
subunits. Cleavage at upstream Site 1 is followed by the proteolytic
excision of an intervening C peptide region terminating at a downstream
Site 2. Although present evidence suggests that Site 1 lies between
amino acid residues 303 and 317, the mechanism and exact amino acid(s)
involved in cleavage are unknown. Previous amino acid substitutions at
Site 1 failed to abrogate cleavage. We, therefore, performed deletion
mutations within this region. Cleavage of cell surface TSHR, detected
by 125I-TSH cross-linking to intact cells, was not
prevented by deletion of four individual segments within the Site 1
cleavage region (
305–308, 309–312,
313–316, 317–320). However, deletion of
the entire region (305–320) reduced the extent of
cleavage and shifted the cleavage site upstream of the glycan at amino
acid residue N302. Elimination of this glycan
(N302Q substitution) reversed the effect of deleting amino
acid residues 305–320 on TSHR cleavage, suggesting that reduced
cleavage at the new, upstream cleavage site was caused by steric
hindrance by the glycan at N302. In summary, deletion, as
opposed to mutagenesis, of the TSHR cleavage Site 1 region produces a
spatial shift in TSHR cleavage Site 1 from downstream to upstream of
the glycan at N302. These observations provide strong
evidence that TSHR cleavage at this site does not occur at a particular
amino acid motif and suggests that cleavage involves a "molecular
ruler" mechanism involving cleavage at a fixed distance from a
protease attachment site.
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