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Originally published In Press as doi:10.1074/jbc.M100717200 on May 16, 2001

J. Biol. Chem., Vol. 276, Issue 31, 28650-28658, August 3, 2001
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Multiple Sites of Contact between the Carboxyl-terminal Binding Domain of PTHrP-(1-36) Analogs and the Amino-terminal Extracellular Domain of the PTH/PTHrP Receptor Identified by Photoaffinity Cross-linking*

Robert C. GensureDagger §, Thomas J. GardellaDagger , and Harald JüppnerDagger

From the Dagger  Endocrine Unit and the § Pediatric Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

The carboxyl-terminal portions of parathyroid hormone (PTH)-(1-34) and PTH-related peptide (PTHrP)-(1-36) are critical for high affinity binding to the PTH/PTHrP receptor (P1R), but the mechanism of receptor interaction for this domain is largely unknown. To identify interaction sites between the carboxyl-terminal region of PTHrP-(1-36) and the P1R, we prepared analogs of [I5,W23,Y36]PTHrP-(1-36)-amide with individual p-benzoyl-L-phenylalanine (Bpa) substitutions at positions 22-35. When tested with LLC-PK1 cells stably transfected with human P1R (hP1R), the apparent binding affinity and the EC50 of agonist-stimulated cAMP accumulation for each analog was, with the exception of the Bpa24-substituted analog, similar to that of the parent compound. The radiolabeled Bpa23-, Bpa27-, Bpa28-, and Bpa33-substituted compounds affinity-labeled the hP1R sufficiently well to permit subsequent mapping of the cross-linked receptor region. Each of these peptides cross-linked to the amino-terminal extracellular domain of the P1R: [I5,Bpa23,Y36]PTHrP-(1-36)-amide cross-linked to the extreme end of this domain (residues 33-63); [I5,W23,Bpa27,Y36]PTHrP-(1-36)-amide cross-linked to residues 96-102; [I5,W23,Bpa28,Y36]PTHrP-(1-36)- amide cross-linked to residues 64-95; and [I5,W23, Bpa33,Y36]PTHrP-(1-36)-amide cross-linked to residues 151-172. These data thus predict that residues 23, 27, 28, and 33 of native PTHrP are each near to different regions of the amino-terminal extracellular receptor domain of the P1R. This information helps define sites of proximity between several ligand residues and this large receptor domain, which so far has been largely excluded from models of the hormone-receptor complex.

* This work was supported by National Institutes of Health Grant DK11794, National Research Service Award 1F32DK10034-01, a grant from the Endocrine Fellows Foundation, and a grant from Lilly Research Laboratories (to R. C. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Tel.: 617-726-3966; Fax: 617-726-7543; E-mail: jueppner@helix.mgh.harvard.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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