The transforming growth factor beta (TGF?) superfamily is composed of 42 structurally related polypeptide growth factors that perform various functions in humans. All of the members of the TGF3 superfamily signal through a distinct set of extracellular receptors commonly known as the type I and type II receptors. The prototypic members of the superfamily are the TGF?s: TGFB?1, 2, and 3. Signaling is initiated when the igand binds to the type II receptor with subsequent recruitment of the type I receptor forming the mature signaling complex. Both TGF?1 and 3 have intrinsically high affinity for the type II receptor (T?RII) and are able to initiate signaling without any assistance. TGF?2, on the other hand, binds very weakly to the type II receptor. The intrinsically low binding affinity of TGF?2 for TBRII is compensated through the use of an accessory receptor, betaglycan. Betaglycan's role in TGF?2 signaling is to present TGF?2 to T?RII by increasing the intrinsically low affinity of TGF?2 for T(3RII through the formation of a TGF?2:betaglycan:TBRII ternary complex. The TGF? type I receptor (T?RI) is recruited to the complex, betaglycan is displaced, forming the mature signaling complex. Although it is known that betaglycan is required for TGF?2 signaling, the mechanism of complex assembly is not. Betaglycan's extracellular domain is composed of two separate sub-domains, each capable of promoting TGF(3 induced rSMAD phosphorylation. Implying that each half of the extracellular domain betaglycan can independently present TGF?2 to T?RII. The membrane-distal half is referred to as the endoglin-related region (BGE) and the membrane-proximal half is referred to as uromodulin-related region (BGU). While both regions are able to bind TGFB, BGU is also capable of binding inhibin. In combination with the fact that inhibin binding is solely restricted to BGU, it also implies that each half may play a different role in TGF 3 signaling. BGE was selected for study since it is solely capable promoting TGF?2 signaling. To further our understanding of betaglycan's mechanism of presentation, the solution structure of the Endoglin-related region of betaglycan (BGE) will be determined using solution NMR spectroscopy with the complementing crystal structure of BGE in complex with TGFB2 and T?RII. In parallel, native gel shift assays and surface plasmon resonance binding studies will be used to examine the influence BGE has on the binding of T?RII. TGF?2 has been found to play crucial roles in tooth development, it has also been implicated in tumorigenesis of odontogenic neoplasms, and TGF?2 knockout mice develop cleft palate. Understanding the structural and functional role betaglycan plays in TGF(32 signaling, it will give vital insight into craniofacial development. ? ? ?
