Designer TGFβ superfamily ligands with diversified functionality
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...
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| Veröffentlicht in: | PloS one 2011-11, Vol.6 (11), p.e26402-e26402 |
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| creator | Allendorph, George P Read, Jessica D Kawakami, Yasuhiko Kelber, Jonathan A Isaacs, Michael J Choe, Senyon |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0026402 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0026402</identifier><identifier>PMID: 22073163</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activin ; Amino Acid Sequence ; Biology ; Bone morphogenetic protein 2 ; Drosophila ; Intracellular signalling ; Kinases ; Laboratories ; Ligands ; Molecular Sequence Data ; Noggin protein ; Proteins ; Rodents ; Sequence Homology, Amino Acid ; Signal Transduction ; Stem cells ; Transforming Growth Factor beta - metabolism ; Transforming growth factor-b</subject><ispartof>PloS one, 2011-11, Vol.6 (11), p.e26402-e26402</ispartof><rights>2011 Allendorph et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22073163</pmid><doi>10.1371/journal.pone.0026402</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Activin Amino Acid Sequence Biology Bone morphogenetic protein 2 Drosophila Intracellular signalling Kinases Laboratories Ligands Molecular Sequence Data Noggin protein Proteins Rodents Sequence Homology, Amino Acid Signal Transduction Stem cells Transforming Growth Factor beta - metabolism Transforming growth factor-b |
| title | Designer TGFβ superfamily ligands with diversified functionality |
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