Binding Affinity of Transforming Growth Factor-β for Its Type II Receptor Is Determined by the C-terminal Region of the Molecule

A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

“…The structure of the monomer of TGF-␤1 is composed of two antiparallel two-stranded ␤-sheets tightly bound by a cysteine knot and two disulfide bridges forming a ring with a third disulfide bridge that passes through both (22). Two loops protrude from the core of the protein, the first one between the first and second strand (amino acids [25][26][27][28][29][30][31][32][33][34][35] and the second one between the third and fourth strand (amino acids 90 -98). These two loops and an N-terminal helix have been proposed, according to the 3D structures of different TGF-␤ isoforms, to be involved in receptor recognition (24).…”

“…These two loops and an N-terminal helix have been proposed, according to the 3D structures of different TGF-␤ isoforms, to be involved in receptor recognition (24). In addition, mutations of amino acids 92-98 prevent an interaction of TGF-␤1 with its type II receptor (28,29). In the present study, we have found five residues of TGF-␤1 located in these two loops (Lys 31 , His 34 , Glu 35 , Tyr 91 , and Lys 94 ) with equivalent biophysical properties and similar spatial positions in T␤R-I-ECD.…”

Identification of Two Amino Acids in Activin A That Are Important for Biological Activity and Binding to the Activin Type II Receptors

“…Lys-102 is positioned in a region (loop 2) of the ligand previously shown to be important for high affinity binding of TGF-␤1 to T␤RII (21). Other approaches, using antagonistic peptides that block binding of TGF-␤ to its receptors, have defined the W/RXXD motif of the N-terminal segment of the long ␣-helix of TGF-␤s as a primary determinant for receptor binding (41).…”

“…Mutation analysis revealed that the nine cysteines, including the seven conserved cysteines in the family, of mature activin A are essential for either the biosynthesis or the (full) biological activity of activin A (20), and that a phenylalanine to isoleucine substitution at position 21 of activin B creates a dominantinterfering protein (16). In mature TGF-␤1, the C-terminal portion (amino acids 83-112) has recently been defined as necessary for high affinity binding to the TGF-␤ receptor type II (T␤RII) (21). In addition, frameshift and/or point mutations (i.e.…”

Medical Applications of Transforming Growth Factor-

“…25,26 Amino acids 67 and 68 determine the affinity of the TGF-β isoforms for the GPI-linked protein on vascular endothelial cells. 27 Amino acids 92-98 regulate binding of TGF-β to the TGF-β type II receptor (TβRII), 28 with amino acid 94 directly binding TβRII. 29,30 …”