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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Biol+Chem 2017 ; 292 (17): 7173-88 Nephropedia Template TP
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An engineered transforming growth factor ? (TGF-?) monomer that functions as a dominant negative to block TGF-? signaling #MMPMID28228478
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[Apr]; 292 (17): 7173-88 PMID28228478show ga
The transforming growth factor ? isoforms, TGF-?1, -?2, and -?3, 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-? pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-?s in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-? monomer, lacking the heel helix, a structural motif essential for binding the TGF-? type I receptor (T?RI) but dispensable for binding the other receptor required for TGF-? signaling, the TGF-? type II receptor (T?RII), as an alternative therapeutic modality for blocking TGF-? signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-? monomers and bound T?RII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-? signaling with a Ki of 20?70 nm. Investigation of the mechanism showed that the high affinity of the engineered monomer for T?RII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit T?RI, enabled it to bind endogenous T?RII but prevented it from binding and recruiting T?RI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-? signaling and may inform similar modifications of other TGF-? family members.