Regulation of bone morphogenetic protein-4 activity by sequence elements within the prodomain

Shailaja Sopory, Sylvia Nelsen, Catherine Degnin, Crispin Wong, Jan L. Christian

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Bone morphogenetic protein-4 (BMP-4) is synthesized as a large precursor protein, which undergoes proprotein convertase-mediated proteolytic maturation along the secretory pathway to release the active ligand. Pro-BMP-4 is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site). This sequential cleavage liberates a small, evolutionarily conserved, prodomain fragment (the linker peptide) of unknown fate and function. Here we show that the linker domain is essential for proper folding, exit from the endoplasmic reticulum, and thus cleavage of the BMP-4 precursor when overexpressed in Xenopus oocytes and embryos but not in cultured mammalian cells. Mature BMP-4 synthesized from a precursor in which the S1 site is non-cleavable, such that the linker domain remains covalently attached to the ligand, has little or no activity in vivo. Finally, analysis of folding, cleavage, and bioactivity of chimeric precursors containing the BMP-7 prodomain and BMP-4 mature domain, or vice versa, with or without the BMP-4 linker domain revealed that the linker domain is only functional in the context of the BMP-4 prodomain, and that differential cleavage around this domain can regulate the activity of a heterologous ligand.

Original languageEnglish (US)
Pages (from-to)34021-34031
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number45
DOIs
StatePublished - Nov 10 2006

Fingerprint

Bone Morphogenetic Protein 4
Ligands
Protein Precursors
Proprotein Convertases
Bone Morphogenetic Protein 7
Furin
Peptide Fragments
Secretory Pathway
Xenopus
Bioactivity
Endoplasmic Reticulum
Oocytes
Cultured Cells
Embryonic Structures
Cells
Peptides

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of bone morphogenetic protein-4 activity by sequence elements within the prodomain. / Sopory, Shailaja; Nelsen, Sylvia; Degnin, Catherine; Wong, Crispin; Christian, Jan L.

In: Journal of Biological Chemistry, Vol. 281, No. 45, 10.11.2006, p. 34021-34031.

Research output: Contribution to journalArticle

Sopory, Shailaja ; Nelsen, Sylvia ; Degnin, Catherine ; Wong, Crispin ; Christian, Jan L. / Regulation of bone morphogenetic protein-4 activity by sequence elements within the prodomain. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 45. pp. 34021-34031.
@article{5d9e1cf82b24452fb03cca5437de3df4,
title = "Regulation of bone morphogenetic protein-4 activity by sequence elements within the prodomain",
abstract = "Bone morphogenetic protein-4 (BMP-4) is synthesized as a large precursor protein, which undergoes proprotein convertase-mediated proteolytic maturation along the secretory pathway to release the active ligand. Pro-BMP-4 is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site). This sequential cleavage liberates a small, evolutionarily conserved, prodomain fragment (the linker peptide) of unknown fate and function. Here we show that the linker domain is essential for proper folding, exit from the endoplasmic reticulum, and thus cleavage of the BMP-4 precursor when overexpressed in Xenopus oocytes and embryos but not in cultured mammalian cells. Mature BMP-4 synthesized from a precursor in which the S1 site is non-cleavable, such that the linker domain remains covalently attached to the ligand, has little or no activity in vivo. Finally, analysis of folding, cleavage, and bioactivity of chimeric precursors containing the BMP-7 prodomain and BMP-4 mature domain, or vice versa, with or without the BMP-4 linker domain revealed that the linker domain is only functional in the context of the BMP-4 prodomain, and that differential cleavage around this domain can regulate the activity of a heterologous ligand.",
author = "Shailaja Sopory and Sylvia Nelsen and Catherine Degnin and Crispin Wong and Christian, {Jan L.}",
year = "2006",
month = "11",
day = "10",
doi = "10.1074/jbc.M605330200",
language = "English (US)",
volume = "281",
pages = "34021--34031",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "45",

}

TY - JOUR

T1 - Regulation of bone morphogenetic protein-4 activity by sequence elements within the prodomain

AU - Sopory, Shailaja

AU - Nelsen, Sylvia

AU - Degnin, Catherine

AU - Wong, Crispin

AU - Christian, Jan L.

PY - 2006/11/10

Y1 - 2006/11/10

N2 - Bone morphogenetic protein-4 (BMP-4) is synthesized as a large precursor protein, which undergoes proprotein convertase-mediated proteolytic maturation along the secretory pathway to release the active ligand. Pro-BMP-4 is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site). This sequential cleavage liberates a small, evolutionarily conserved, prodomain fragment (the linker peptide) of unknown fate and function. Here we show that the linker domain is essential for proper folding, exit from the endoplasmic reticulum, and thus cleavage of the BMP-4 precursor when overexpressed in Xenopus oocytes and embryos but not in cultured mammalian cells. Mature BMP-4 synthesized from a precursor in which the S1 site is non-cleavable, such that the linker domain remains covalently attached to the ligand, has little or no activity in vivo. Finally, analysis of folding, cleavage, and bioactivity of chimeric precursors containing the BMP-7 prodomain and BMP-4 mature domain, or vice versa, with or without the BMP-4 linker domain revealed that the linker domain is only functional in the context of the BMP-4 prodomain, and that differential cleavage around this domain can regulate the activity of a heterologous ligand.

AB - Bone morphogenetic protein-4 (BMP-4) is synthesized as a large precursor protein, which undergoes proprotein convertase-mediated proteolytic maturation along the secretory pathway to release the active ligand. Pro-BMP-4 is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site). This sequential cleavage liberates a small, evolutionarily conserved, prodomain fragment (the linker peptide) of unknown fate and function. Here we show that the linker domain is essential for proper folding, exit from the endoplasmic reticulum, and thus cleavage of the BMP-4 precursor when overexpressed in Xenopus oocytes and embryos but not in cultured mammalian cells. Mature BMP-4 synthesized from a precursor in which the S1 site is non-cleavable, such that the linker domain remains covalently attached to the ligand, has little or no activity in vivo. Finally, analysis of folding, cleavage, and bioactivity of chimeric precursors containing the BMP-7 prodomain and BMP-4 mature domain, or vice versa, with or without the BMP-4 linker domain revealed that the linker domain is only functional in the context of the BMP-4 prodomain, and that differential cleavage around this domain can regulate the activity of a heterologous ligand.

UR - http://www.scopus.com/inward/record.url?scp=33845944389&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845944389&partnerID=8YFLogxK

U2 - 10.1074/jbc.M605330200

DO - 10.1074/jbc.M605330200

M3 - Article

C2 - 16966322

AN - SCOPUS:33845944389

VL - 281

SP - 34021

EP - 34031

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -