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Development. 2014 Aug;141(15):3062-71. doi: 10.1242/dev.110130. Epub 2014 Jul 3.

Simultaneous rather than ordered cleavage of two sites within the BMP4 prodomain leads to loss of ligand in mice.

Author information

1
Department of Cell and Developmental Biology, Oregon Health and Sciences University, School of Medicine, Portland, OR 97239-3098, USA.
2
Department of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, School of Medicine, Salt Lake City, UT 94132, USA.
3
Department of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, School of Medicine, Salt Lake City, UT 94132, USA jan.christian@neuro.utah.edu.

Abstract

ProBMP4 is generated as a latent precursor that is sequentially cleaved at two sites within the prodomain to generate an active ligand. An initial cleavage occurs adjacent to the ligand domain, which generates a non-covalently associated prodomain/ligand complex that is subsequently dissociated by cleavage at an upstream site. An outstanding question is whether the two sites need to be cleaved sequentially and in the correct order to achieve proper control of BMP4 signaling during development. In the current studies, we demonstrate that mice carrying a knock-in point mutation that causes simultaneous rather than sequential cleavage of both prodomain sites show loss of BMP4 function and die during mid-embryogenesis. Levels of mature BMP4 are severely reduced in mutants, although levels of precursor and cleaved prodomain are unchanged compared with wild type. Our biochemical analysis supports a model in which the transient prodomain/ligand complex that forms during sequential cleavage plays an essential role in prodomain-mediated stabilization of the mature ligand until it can acquire protection from degradation by other means. By contrast, simultaneous cleavage causes premature release of the ligand from the prodomain, leading to destabilization of the ligand and loss of signaling in vivo.

KEYWORDS:

Bone morphogenetic protein 4; Prodomain; Proprotein convertase

PMID:
24993941
PMCID:
PMC4197676
DOI:
10.1242/dev.110130
[Indexed for MEDLINE]
Free PMC Article

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