title: Designer TGFβ superfamily ligands with diversified functionality.
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.
authors.affiliation: Joint Center for Biosciences at Lee Gil Ya Cancer and Diabetes Institute, Gachon University for Medicine and Science, Incheon, Korea.
authors.forename: George P
authors.initials: GP
authors.lastname: Allendorph
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Read
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kelber
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Isaacs
authors.forename: Senyon
authors.initials: S
authors.lastname: Choe
mesh_terms: D000595:Amino Acid Sequence; D008024:Ligands; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D008024:Ligands; D016212:Transforming Growth Factor beta
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