| Abstrakt: |
How receptors juggle their interactions with multiple downstream effectors remains poorly understood. Here we show that the outcome of death receptor p75NTR signaling is determined through competition of effectors for interaction with its intracellular domain, in turn dictated by the nature of the ligand. While NGF induces release of RhoGDI through recruitment of RIP2, thus decreasing RhoA activity in favor of NFkB signaling, MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, disengaging RIP2, and enhancing RhoA activity in detriment of NF-kB. This results in stunted neurite outgrowth and apoptosis in cerebellar granule neurons. If presented simultaneously, MAG prevails over NGF. The NMR solution structure of the complex between the RhoGDI N-terminus and p75NTR juxtamembrane domain reveals previously unknown structures of these proteins and clarifies the mechanism of p75NTR activation. These results show how ligand-directed competition between RIP2 and RhoGDI for p75NTR engagement determine axon growth and neuron survival. Similar principles are likely at work in other receptors engaging multiple effectors and signaling pathways. Synopsis: MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, locking p75NTR in a configuration that promotes RhoA activity, growth cone collapse, stunted neurite outgrowth, and neuronal apoptosis. MAG induces PKC-mediated phosphorylation of RhoGDI at Ser34, leading to phosphorylation at Ser96, which results in the release and activation of RhoA. Phosphorylated Ser34 interacts in trans with Lys303 of the p75NTR juxtamembrane domain, which becomes structured by wrapping around RhoGDI N-terminal domain. Fully phosphorylated RhoGDI outcompetes RIP2 and locks p75NTR in a configuration that promotes growth cone collapse, stunted neurite outgrowth, and apoptosis in cerebellar granule neurons. MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, locking p75NTR in a configuration that promotes RhoA activity, growth cone collapse, stunted neurite outgrowth, and neuronal apoptosis. [ABSTRACT FROM AUTHOR] |
