Comparison of nerve growth factor receptor binding models using heterodimeric muteins

摘要: Nerve growth factor (NGF) is a homodimer that binds to two distinct receptor types, TrkA and p75, support survival differentiation of neurons. The high-affinity binding on the cell surface believed involve heteroreceptor complex, but its exact nature unclear. We developed heterodimer (heteromutein) NGF muteins can bind p75 opposite sides heterodimer, not receptors. Previously described are Δ9/13 negative 7-84-103 signal selective through TrkA. heteromutein (Htm1) was used study complex formation function, in putative absence NGF-induced dimerization. Cellular assays indicated Htm1 does as efficiently wild-type (wt) has better affinity than either homodimeric mutein. Htm1, 7-84-103, were each able compete for cold-temperature, cold-chase stable PC12 cells, indicating required portion this binding. Survival, neurite outgrowth, MAPK signaling cells also showed reduced response compared with wtNGF, parent order wtNGF > >> Δ9/13. demonstrated similar levels expressing only In longstanding debate mechanism, our data ligand passing from involving transient p75-NGF-TrkA.