Functional properties of a synthetic chicken parathyroid hormone-related protein 1-36 fragment.
The biologic activities of human parathyroid hormone-related protein [hPTHrP(1-34] and bovine PTH [bPTH(1-34)] are remarkably similar despite marked sequence divergence in their primary binding domain, residues 25-34. Chicken PTHrP (cPTHrP) is identical to hPTHrP through residue 21. However, in the 25-34 region, cPTHrP displays three fewer basic residues than hPTHrP and contains five residues not present in any other member of the PTH/PTHrP family. To assess the biologic consequences of these structural differences, we compared the activities of synthetic [36Tyr]cPTHrP(1-36)NH2 and hPTHrP(1-34)NH2 with those of bPTH(1-34) in avian systems (chicken renal plasma membranes and 19 day chick embryonic bone cells) and mammalian systems [canine renal plasma membranes and rat osteosarcoma cells (UMR-106-H5)]. In both avian and mammalian systems the binding affinity of [36Tyr]cPTHrP(1-36)NH2 (0.8-3.4 nM) was approximately one-half that of hPTHrP(1-34)NH2 (0.4-1.1 nM). The potencies of [36Tyr]cPTHrP(1-36)NH2 and hPTHrP(1-34)NH2 for activation of adenylate cyclase were similar in canine renal membranes (5.2 and 6.7 nM) and chick bone cells (1.0 nM). In UMR-106 cells and chicken renal membranes the potency of [36Tyr[cPTHrP(1-36)NH2 for activation of adenylate cyclase was about one-half that of [36Tyr]hPTHrP(1-36)NH2. Binding of 125I-[36Tyr]cPTHrP(1-36)NH2 to chick bone cells and chicken renal membranes was completely displaced by bPTH(1-34) and hPTHrP(1-34)NH2: thus there was no evidence for a distinct chicken PTHrP receptor. In general, [36Tyr]cPTHrP(1-36)NH2 and hPTHrP(1-34)NH2 activated adenylate cyclase similarly despite their sequence differences in the 25-32 region.(ABSTRACT TRUNCATED AT 250 WORDS)
Schermer
D T
DT
Endocrine Unit, Veterans Administration Medical Center, San Francisco, California.
Bradley
M S
MS
Bambino
T H
TH
Nissenson
R A
RA
Strewler
G J
GJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D003432:Cross-Linking Reagents; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D019379:Teriparatide / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D018016:Receptors, Parathyroid Hormone; C079957:parathyroid hormone-related peptide (1-36); D019379:Teriparatide; C025076:parathyroid hormone (1-34), bovine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C035748:parathyroid hormone (1-34)amide