Conformational landscape of full-length Smad proteins

Abstract

Smad transcription factors, the main effectors of the TGFβ (transforming growth factor β) network, have been shaped along the evolution of multicellular animals to regulate essential processes. Smad proteins have a mixed architecture of globular domains and flexible linkers and adopt distinct quaternary structures depending on their activation state and cellular context. Here we studied the structures of full-length Smad4 and Smad2 proteins through an integrative approach combining small-angle X-ray scattering and detailed atomic information obtained from Nuclear Magnetic Resonance spectroscopy, X-ray and molecular dynamic simulations. Both Smad4 and Smad2 populate ensembles of expanded/compact conformations, with the MH1 and MH2 domains tethered by intrinsically disordered linkers that provide conformational freedom to the proteins. In solution, Smad4 is monomeric, whereas Smad2 coexists as monomer-dimer-trimer association states, even without activation. Smad2 dimers, which were previously overlooked, are proposed as key building blocks that define the functional quaternary structures of Smad proteins.

Intrinsically disordered proteins play diverse roles in cell signaling

“…A final type of cell signaling regulated transcription factor includes Smad proteins, which are regulated by TGFβ/ BMP signaling. These transcription factors are composed of two structured domains separate by an intrinsically disordered linker, allowing the protein structure to range between compact and extended structures [325]. Smad dynamics are hypothesized to be important for modulating Smad function and thus signal transduction.…”