5tx6
Structure of TGF-beta2 derivative with deletion of residues 52-71 and 10 single amino acid mutations (mmTGF-beta2-7M)
Structural highlights
FunctionTGFB2_MOUSE TGF-beta 2 has suppressive effects on interleukin-2 dependent T-cell growth. Publication Abstract from PubMedThe transforming growth factor beta isoforms, TGF-beta1, -beta2, and -beta3 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-beta pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. In spite of the known importance of TGF-betas in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-beta monomer, lacking the heel helix, a structural motif essential for binding the TGF-beta type I receptor, TbetaRI, but dispensible for binding the other receptor required for TGF-beta signaling, the TGF-beta type II receptor, TbetaRII, as an alternative therapeutic modality for blocking TGF-beta signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-beta monomers and bound TbetaRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-beta signaling with a Ki of 20 - 70 nM. Investigation of the mechanism showed that the high affinity of the engineered monomer for TbetaRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TbetaRI, enabled it to bind endogenous TbetaRII, but prevented it from binding and recruiting TbetaRI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-beta signaling, and may inform similar modifications of other TGF-beta family members. An Engineered TGF-beta Monomer that Functions as a Dominant Negative to Block TGF-beta Signaling.,Kim SK, Barron L, Hinck CS, Petrunak EM, Cano KE, Thangirala A, Iskra B, Brothers M, Vonberg M, Leal B, Richter B, Kodali R, Taylor AB, Du S, Barnes CO, Sulea T, Calero G, Hart PJ, Hart MJ, Demeler B, Hinck AP J Biol Chem. 2017 Feb 22. pii: jbc.M116.768754. doi: 10.1074/jbc.M116.768754. PMID:28228478[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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