The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif.

ZFYVE16（endofin）促进了Smad杂漆形成。ZFYVE16可以结合TGFBR1并促进SMAD2磷酸化，并且还可以结合SMAD4，但是ZFYVE16（endofin）作用在TGF-β受体信号传导的上下文中的确切机制不知道（Chen等，2007）。