Conformational studies of parathyroid hormone (PTH)/PTH-related protein (PTHrP) point-mutated hybrids

✍ Scribed by Evaristo Peggion; Stefano Mammi; Elisabetta Schievano; Vered Behar; Michael Rosenblatt; Michael Chorev

• Publisher: Wiley (John Wiley & Sons)
• Year: 1999
• Tongue: English
• Weight: 191 KB
• Volume: 50
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/(sici)1097-0282(19991015)50:5<525::aid-bip6>3.0.co;2-8

✦ Synopsis

The N-terminal 1-34 segments of both parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) bind and activate the same membrane receptor in spite of major differences between the two hormones in their amino acid sequence. Recently, it was shown that in (1-34)PTH/PTHrP segmental hybrid peptides, the N-terminal 1-14 segment of PTHrP is incompatible with the C-terminal 15-34 region of PTH leading to substantial reduction in potency. The sites of incompatibility were identified as positions 5 in PTH and 19 in PTHrP. In the present paper we describe the synthesis, biological evaluation, and conformational characterization of two point-mutated PTH/ PTHrP 1-34 hybrids in which the arginine residues at positions 19 and 21 of the native sequence of PTHrP have been replaced by valine (hybrid V 21 ) and glutamic acid (hybrid E 19 ), respectively, taken from the PTH sequence. Hybrid V 21 exhibits both high receptor affinity and biological potency, while hybrid E 19 binds weakly and is poorly active. The conformational properties of the two hybrids were studied in aqueous solution containing dodecylphosphocholine (DPC) micelles and in water/2,2,2trifluoroethanol (TFE) mixtures. Upon addition of TFE or DPC micelles to the aqueous solution, both