ИСТИНА

Neurotrophins are key regulators of the nervous system. They bind to the common p75 neurotrophin receptor (p75NTR) that in turn interacts with RIP2, TRAF6, RhoGDI etc and different signaling pathways are initiated. The expression of p75NTR correlates with neuronal insult, axonal degeneration and dysfunction during cellular stress. This makes p75NTR a potential target for the therapy for several diseases. Despite many studies on this receptor in various functional states, the molecular mechanisms are still unclear. The structural data can shed light on the function of this receptor. The p75NTR is a type I integral membrane protein. It is composed of an extracellular ligand­binding domain, a single­span helical transmembrane domain (TMD), and an intracellular domain (ICD) containing so­called death domain. There are spatial structures of each domain of p75NTR but the key problem of understanding the structural­functional relationship is the patchy knowledge about the full­length receptor. The investigation of full­length membrane protein using any structural method is a very difficult task today. Here we demonstrate the next evolution step of the receptor investigation ­ the two­domain system including TMD and ICD domains. The key advantage of this system is a possibility to study the influence of the TMD structural rearrangements or oligomerization on the functional activity of intracellular domain. We present our structural data for p75NTR and RIP2 and different membrane mimetics that could be applied in the study of the receptor interaction using NMR. The obtained data are discussed in the context of the receptor activation mechanism. The work is supported by Russian Science Foundation (project #14­14­00573).