Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 355, Issue 1, Pages 47-62Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2005.10.022
Keywords
TGF beta; T beta RII; betaglycan; ligand-receptor; alanine scanning
Categories
Funding
- NCI NIH HHS [CA79683, CA54174] Funding Source: Medline
- NCRR NIH HHS [RR13879] Funding Source: Medline
- NIGMS NIH HHS [GM58670] Funding Source: Medline
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TGF 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 IIe53 and Glu119, which contact TGF beta 3 Va192 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, lle92, 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. (c) 2005 Elsevier Ltd. All rights reserved.
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