Elimination of the carboxy-terminal sequences of parathyroid hormone-related protein 1-173 increases production and secretion of the truncated forms

Endocrinology
L S DitmerL J Deftos

Abstract

The endoproteolytic processing of polypeptides at basic residues into distinct biologically active peptides is a common theme in prohormone maturation and processing. PTH-related protein (PTHrP) 1-173 contains eight putative endoproteolytic consensus sites that include a mono-arginyl (R37), paired basic (RR154-155), and related basic residue motifs (RLKR-4 to -1, RRR19-21, KKKK88-91, KRK96-98, KKKRR102-106, and KKKK147-150). To analyze the primary structural determinants involved in the posttranslational processing and secretion of PTHrP 1-173, we constructed a series of nonsense mutants that code for carboxy-terminal truncated polypeptides. Since the basic residue motifs are probable sites of endoproteolysis, these sites and the residues downstream were serially eliminated, thereby creating PTHrP 1-152, 1-146, 1-101, 1-95, 1-87, 1-36, and 1-18. The wild type PTHrP 1-173 and nonsense mutant constructs were transiently transfected into two cell lines, COS-1 and SK-N-BE(2). The COS-1 cells have a constitutive secretory pathway, whereas the neuroblastoma-derived BE-2 cells have, in addition, a regulated secretory pathway. PTHrP was measured in the conditioned media and cell extracts of the transfected cells with two peptide-specif...Continue Reading

Citations

Feb 12, 1998·Proceedings of the National Academy of Sciences of the United States of America·T MassfelderA F Stewart
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Jul 28, 2009·American Journal of Physiology. Lung Cellular and Molecular Physiology·Randolph H HastingsErin Healy
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