Formation and characterization of BMP2/GDF5 and BMP4/GDF5 heterodimers

BMC Biology

Research Article

Kristof Nolan¹  Mary C. Mullins²  Joseph Zinski²  Thomas B. Thompson³  Gregory R. Gipson³  Chandramohan Kattamuri³  Magdalena Czepnik³  Aaron M. Zorn⁴  Zachary Agricola⁴  Alan P. Kenny⁴  Nicole A. Edwards⁴ 

[1] Department of Biochemistry and Molecular Biophysics, University of Chicago, Chicago, IL, USA;Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA;Department of Molecular & Cellular Biosciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA;Perinatal Institute, Divisions of Developmental Biology and Neonatology & Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;

关键词: BMP;    Growth factor;    Heterodimer;    Cell signaling;   

DOI  :  10.1186/s12915-023-01522-4

 received in 2022-09-06, accepted in 2023-01-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundProteins of the TGFβ family, which are largely studied as homodimers, are also known to form heterodimers with biological activity distinct from their component homodimers. For instance, heterodimers of bone morphogenetic proteins, including BMP2/BMP7, BMP2/BMP6, and BMP9/BMP10, among others, have illustrated the importance of these heterodimeric proteins within the context of TGFβ signaling.ResultsIn this study, we have determined that mature GDF5 can be combined with mature BMP2 or BMP4 to form BMP2/GDF5 and BMP4/GDF5 heterodimer. Intriguingly, this combination of a BMP2 or BMP4 monomer, which exhibit high affinity to heparan sulfate characteristic to the BMP class, with a GDF5 monomer with low heparan sulfate affinity produces a heterodimer with an intermediate affinity. Using heparin affinity chromatography to purify the heterodimeric proteins, we then determined that both the BMP2/GDF5 and BMP4/GDF5 heterodimers consistently signaled potently across an array of cellular and in vivo systems, while the activities of their homodimeric counterparts were more context dependent. These differences were likely driven by an increase in the combined affinities for the type 1 receptors, Alk3 and Alk6. Furthermore, the X-ray crystal structure of BMP2/GDF5 heterodimer was determined, highlighting the formation of two asymmetric type 1 receptor binding sites that are both unique relative to the homodimers.ConclusionsUltimately, this method of heterodimer production yielded a signaling molecule with unique properties relative to the homodimeric ligands, including high affinity to multiple type 1 and moderate heparan binding affinity.

【 授权许可】

CC BY   
© The Author(s) 2023

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