The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Judith M. Neugebauer, Sunjong Kwon, Hyung Seok Kim, Nathan Donley, Anup Tilak, Shailaja Sopory, Jan L. Christian

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.

Original languageEnglish (US)
Pages (from-to)E2307-E2316
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number18
DOIs
StatePublished - May 5 2015

Fingerprint

Bone Morphogenetic Protein 4
Bone Morphogenetic Protein 7
Ligands
Protein Precursors
Bone Diseases
Embryonic Development
Homeostasis
Wounds and Injuries

Keywords

  • BMP4
  • BMP7
  • Bone morphogenetic protein
  • Heterodimer
  • Prodomain

ASJC Scopus subject areas

  • General

Cite this

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo. / Neugebauer, Judith M.; Kwon, Sunjong; Kim, Hyung Seok; Donley, Nathan; Tilak, Anup; Sopory, Shailaja; Christian, Jan L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 18, 05.05.2015, p. E2307-E2316.

Research output: Contribution to journalArticle

Neugebauer, Judith M. ; Kwon, Sunjong ; Kim, Hyung Seok ; Donley, Nathan ; Tilak, Anup ; Sopory, Shailaja ; Christian, Jan L. / The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 18. pp. E2307-E2316.
@article{0783964bb77248e0b6749b9e89197474,
title = "The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo",
abstract = "Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.",
keywords = "BMP4, BMP7, Bone morphogenetic protein, Heterodimer, Prodomain",
author = "Neugebauer, {Judith M.} and Sunjong Kwon and Kim, {Hyung Seok} and Nathan Donley and Anup Tilak and Shailaja Sopory and Christian, {Jan L.}",
year = "2015",
month = "5",
day = "5",
doi = "10.1073/pnas.1501449112",
language = "English (US)",
volume = "112",
pages = "E2307--E2316",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

AU - Neugebauer, Judith M.

AU - Kwon, Sunjong

AU - Kim, Hyung Seok

AU - Donley, Nathan

AU - Tilak, Anup

AU - Sopory, Shailaja

AU - Christian, Jan L.

PY - 2015/5/5

Y1 - 2015/5/5

N2 - Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.

AB - Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.

KW - BMP4

KW - BMP7

KW - Bone morphogenetic protein

KW - Heterodimer

KW - Prodomain

UR - http://www.scopus.com/inward/record.url?scp=84928942254&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928942254&partnerID=8YFLogxK

U2 - 10.1073/pnas.1501449112

DO - 10.1073/pnas.1501449112

M3 - Article

VL - 112

SP - E2307-E2316

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -