Three Key Residues Underlie the Differential Affinity of the TGF[beta] Isoforms for the TGF[beta] Type II Receptor

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Pages4762; # of pages: 16
Subjectcrystal structure; I; pha; Wound Healing
AbstractTGF[beta]1, [beta]2, and [beta]3 are 25 kDa homodimeric polypeptides that play crucial non-overlapping roles in development, tumor suppression, and wound healing. They exhibit 70-82% sequence identity and transduce their signals by binding and bringing together the TGF[beta] type I and type II receptors, T[beta]RI and T[beta]RII. TGF[beta]2 differs from the other isoforms in that it binds T[beta]RII weakly and is dependent upon the co-receptor betaglycan for function. To explore the physicochemical basis underlying these differences, we generated a series of single amino acid T[beta]RII variants based on the crystal structure of the T[beta]RII:TGF[beta]3 complex and examined these in terms of their TGF[beta] isoform binding affinity and their equilibrium stability. The results showed that T[beta]RII Ile53 and Glu119, which contact TGF[beta]3 Val92 and Arg25, respectively, together with T[beta]RII Asp32, Glu55, and Glu75, which contact TGF[beta]3 Arg94, each contribute significantly, between 1 kcal mol-1 to 1.5 kcal mol-1, to ligand binding affinities. These contacts likely underlie the estimated 4.1 kcal mol-1 lower affinity with which T[beta]RII binds TGF[beta]2 as these three ligand residues are unchanged in TGF[beta]1 but are conservatively substituted in TGF[beta]2 (Lys25, Ile92, and Lys94). To test this hypothesis, a TGF[beta]2 variant was generated in which these three residues were changed to those in TGF[beta]s 1 and 3. This variant exhibited receptor binding affinities comparable to those of TGF[beta]s 1 and 3. Together, these results show that these three residues underlie the lowered affinity of TGF[beta]2 for T[beta]RII and that all isoforms likely induce assembly of the TGF[beta] signaling receptors in the same overall manner
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AffiliationNRC Biotechnology Research Institute; National Research Council Canada
Peer reviewedNo
NRC number47500
NPARC number3539137
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Record identifierb1e28af6-cdcc-4499-8c4a-ef684262e17f
Record created2009-03-01
Record modified2016-05-09
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