Ion channels have been long recognized as one of the largest cell signaling superfamilies, underlying numerous critical health related phenomena. Dynamic allosteric processes in ion channels control key aspects of signaling, including inactivation and mean open time. Solid state NMR experiments on full length wild type channel in proteo-liposomes provide evidence for evacuation of ions from the selectivity filter during inactivation and thermodynamic coupling between channel opening and ion affinity. Furthermore, these experiments have identified residues that serve as “hotspots” for allostery. We examine an intermediate of the opening process and its conformational exchange processes. We also report progress on very high order oligomeric proteins including amyloids are increasingly seen to be involved in cell signaling in human health and disease. We study several examples, including formation of the RIPK1:RIPK3 complex and the necrosome which is a key commitment complex for TNF-induced necroptosis in the context of immune defense, cancer and neurodegenerative diseases. Using solid-state NMR, we determined the high-resolution structure of the necrosome core. RIPK1 and RIPK3 assume serpentine conformations, with short β-segments. Packing analogous to other amyloids results in a hydrophobic core with both hetero and homo hydrophobic contacts, and unusual exposed “ladders” of interacting amino acids. This molecularly detailed structure of a hetero-oligomeric amyloid and provides insights into the mechanisms of signal transduction and of inhibition of necroptosis, appears to represent a large family of analogous complexes including those involved in response to viral infection.