An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling
Abstract
The transforming growth factor β isoforms, TGF-β1, -β2, and -β3, are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor (TβRI) but dispensable for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor (TβRII), as an alternative therapeutic modality for blocking TGF-β signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-β monomers and bound TβRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-β signaling with a Ki of 20–70 nM. Investigation of the mechanism showed that the high affinity of the engineered monomer for TβRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TβRI,more »
- Authors:
-
more »
- Univ. of Texas Health Science Center, San Antonio, TX (United States)
- Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States)
- Human Health Therapeutics Portfolio, Montreal, QC (Canada)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Inst. of Health; Robert A. Welch Foundation; National Science Foundation (NSF); Cancer Prevention Research Inst.; American Heart Assoc.
- OSTI Identifier:
- 1355043
- Grant/Contract Number:
- GM58670; CA172886; AQ1842; P30 CA54174; GM120600; ACI-1339649; RP1450105; 15PRE25550015
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 292; Journal Issue: 17; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; cancer; cell signaling; fibrosis; inhibitor; protein engineering; transforming growth factor beta (TGF-B); dominant negative
Citation Formats
Kim, Sun Kyung, Barron, Lindsey, Hinck, Cynthia S., Petrunak, Elyse M., Cano, Kristin E., Thangirala, Avinash, Iskra, Brian, Brothers, Molly, Vonberg, Machell, Leal, Belinda, Richter, Blair, Kodali, Ravindra, Taylor, Alexander B., Du, Shoucheng, Barnes, Christopher O., Sulea, Traian, Calero, Guillermo, Hart, P. John, Hart, Matthew J., Demeler, Borries, and Hinck, Andrew P. An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling. United States: N. p., 2017.
Web. doi:10.1074/jbc.M116.768754.
Kim, Sun Kyung, Barron, Lindsey, Hinck, Cynthia S., Petrunak, Elyse M., Cano, Kristin E., Thangirala, Avinash, Iskra, Brian, Brothers, Molly, Vonberg, Machell, Leal, Belinda, Richter, Blair, Kodali, Ravindra, Taylor, Alexander B., Du, Shoucheng, Barnes, Christopher O., Sulea, Traian, Calero, Guillermo, Hart, P. John, Hart, Matthew J., Demeler, Borries, & Hinck, Andrew P. An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling. United States. https://doi.org/10.1074/jbc.M116.768754
Kim, Sun Kyung, Barron, Lindsey, Hinck, Cynthia S., Petrunak, Elyse M., Cano, Kristin E., Thangirala, Avinash, Iskra, Brian, Brothers, Molly, Vonberg, Machell, Leal, Belinda, Richter, Blair, Kodali, Ravindra, Taylor, Alexander B., Du, Shoucheng, Barnes, Christopher O., Sulea, Traian, Calero, Guillermo, Hart, P. John, Hart, Matthew J., Demeler, Borries, and Hinck, Andrew P. Wed .
"An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling". United States. https://doi.org/10.1074/jbc.M116.768754. https://www.osti.gov/servlets/purl/1355043.
@article{osti_1355043,
title = {An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling},
author = {Kim, Sun Kyung and Barron, Lindsey and Hinck, Cynthia S. and Petrunak, Elyse M. and Cano, Kristin E. and Thangirala, Avinash and Iskra, Brian and Brothers, Molly and Vonberg, Machell and Leal, Belinda and Richter, Blair and Kodali, Ravindra and Taylor, Alexander B. and Du, Shoucheng and Barnes, Christopher O. and Sulea, Traian and Calero, Guillermo and Hart, P. John and Hart, Matthew J. and Demeler, Borries and Hinck, Andrew P.},
abstractNote = {The transforming growth factor β isoforms, TGF-β1, -β2, and -β3, are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor (TβRI) but dispensable for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor (TβRII), as an alternative therapeutic modality for blocking TGF-β signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-β monomers and bound TβRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-β signaling with a Ki of 20–70 nM. Investigation of the mechanism showed that the high affinity of the engineered monomer for TβRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TβRI, enabled it to bind endogenous TβRII but prevented it from binding and recruiting TβRI to form a signaling complex. In conclusion, such engineered monomers provide a new avenue to probe and manipulate TGF-β signaling and may inform similar modifications of other TGF-β family members.},
doi = {10.1074/jbc.M116.768754},
journal = {Journal of Biological Chemistry},
number = 17,
volume = 292,
place = {United States},
year = {Wed Feb 22 00:00:00 EST 2017},
month = {Wed Feb 22 00:00:00 EST 2017}
}
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