The tryptophan-rich motifs of the thrombospondin type 1 repeats bind VLAL motifs in the latent transforming growth factor-beta complex

The Journal of Biological Chemistry
Geoffrey D Young, Joanne E Murphy-Ullrich

Abstract

Transforming growth factor-beta (TGF-beta) is secreted as a latent complex of the latency-associated peptide (LAP) and the mature domain, which must be activated for TGF-beta to signal. We previously identified thrombospondin 1 (TSP1) as a physiologic activator of TGF-beta in vitro and in vivo. The WSXW sequences in the type 1 repeats of TSP1 interact with the mature domain of TGF-beta, and WSXW peptides inhibit TSP1-mediated activation by blocking TSP1 binding to the TGF-beta latent complex. However, the binding site for the WSXW sequence was not identified. In this report, we show that the WSXW sequences bind the (61)VLAL sequence in mature TGF-beta and also bind (77)VLAL in LAP. A glutathione S-transferase (GST) fusion protein of the second TSP1 type 1 repeat (GST-TSR2) binds immobilized VLAL peptide. VLAL peptides inhibit binding of LAP and mature TGF-beta to soluble GST-TSR2 and immobilized WSXW peptide. VLAL peptide inhibits TSP1-mediated activation of recombinant and endothelial cell-derived latent TGF-beta. Furthermore, TGF-beta or LAP deleted in the VLAL sequence fails to bind immobilized WSXW or soluble GST-TSR2, indicating that binding to both VLAL sequences is important for association of TSP1 and the latent complex...Continue Reading

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