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Proc Natl Acad Sci U S A. 2015 May 5;112(18):E2307-16. doi: 10.1073/pnas.1501449112. Epub 2015 Apr 20.

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

Author information

1
Departments of Neurobiology and Anatomy and.
2
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University School of Medicine, Portland, OR 97239-3098.
3
Departments of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84132-3401; and jan.christian@neuro.utah.edu.

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

PMID:
25902523
PMCID:
PMC4426409
DOI:
10.1073/pnas.1501449112
[Indexed for MEDLINE]
Free PMC Article

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