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Volume 271, Number 40, Issue of October 4, 1996 pp. 24371-24381
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Structural and Physiologic Characterization of the Mid-region Secretory Species of Parathyroid Hormone-related Protein

(Received for publication, April 23, 1996, and in revised form, July 11, 1996)

Terence L. Wu ^§ , Rupangi C. Vasavada ^§ , Kai Yang ^§ , Thierry Massfelder ^§ , Michael Ganz ^¶ , S. Khawar Abbas , Anthony D. Care and Andrew F. Stewart ^§

From the  Division of Endocrinology, Connecticut Veterans Affairs Medical Center, West Haven, Connecticut 06516, ^§ Section of Endocrinology, Yale University School of Medicine, New Haven Connecticut 06510, ^¶ Division of Nephrology, Cleveland Veterans Affairs Medical Center and Case Western Reserve Medical School, Cleveland Ohio 44106, and  Institute of Biological Sciences, University of Wales, Aberystwyth, SY23 3DD, United Kingdom

Parathyroid hormone-related protein (PTHrP) is initially translated as a preprohormone which is posttranslationally processed to yield a family of mature secretory forms. Most attention has focused on the amino-terminal portion of the molecule which is homologous to parathyroid hormone. It is clear, however, that a mid-region species of PTHrP is posttranslationally cleaved from the highly conserved mid-region of PTHrP, and that the amino terminus of this peptide is Ala³⁸. The purposes of the current study were three: 1) to confirm that Arg³⁷ immediately preceding Ala³⁸ serves as a posttranslational processing site in the PTHrP precursor, 2) to determine the carboxyl terminus of the mid-region secretory species of PTHrP, and 3) to synthesize this authentic mid-region secretory form of PTHrP and determine whether it is biologically active. The results indicate that: 1) Arg³⁷ is indeed a processing site in the PTHrP precursor; 2) three distinct mid-region PTHrP species are generated by posttranslational processing, PTHrP(38-94)amide, PTHrP(38-95), and most likely, PTHrP(38-101); and 3) synthetic mid-region PTHrP(38-94)amide is active in four different biological systems. These studies confirm the finding that PTHrP is a prohormone. More importantly, they define a novel, biologically active highly conserved mid-region secretory form of PTHrP.

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