Designer TGFβ superfamily ligands with diversified functionality

George P. Allendorph, Jessica D. Read, Yasuhiko Kawakami, Jonathan A. Kelber, Michael J. Isaacs, Senyon Choe

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Transforming Growth Factor - beta (TGFβ) superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs), and Bone Morphogenetic Proteins (BMPs), are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer), to engineer chemically-refoldable TGFβ superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-βA and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGFβ superfamily ligands through development of novel chimeric TGFβ ligands with diverse biological and clinical values.

Original languageEnglish (US)
Article numbere26402
JournalPloS one
Volume6
Issue number11
DOIs
StatePublished - Nov 4 2011

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    Allendorph, G. P., Read, J. D., Kawakami, Y., Kelber, J. A., Isaacs, M. J., & Choe, S. (2011). Designer TGFβ superfamily ligands with diversified functionality. PloS one, 6(11), [e26402]. https://doi.org/10.1371/journal.pone.0026402