LINGO-1 protein interacts with the p75 neurotrophin receptor in intracellular membrane compartments

Abstract

Axon outgrowth inhibition in response to trauma is thought to be mediated via the binding of myelin-associated inhibitory factors (e.g. Nogo-66, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, and myelin basic protein) to a putative tripartite LINGO-1·p75 NTR ·Nogo-66 receptor (NgR) complex at the cell surface. We found that endogenous LINGO-1 expression in neurons in the cortex and cerebellum is intracellular. Mutation or truncation of the highly conserved LINGO-1 C terminus altered this intracellular localization, causing poor intracellular retention and increased plasmamembrane expression. p75 NTR associated predominantly with natively expressed LINGO-1 containing immature N-glycans, characteristic of protein that has not completed trans-Golgimediated processing, whereas mutant forms of LINGO-1 with enhanced plasma membrane expression did not associate with p75 NTR. Co-immunoprecipitation experiments demonstrated that LINGO-1 and NgR competed for binding to p75 NTR in a manner that is difficult to reconcile with the existence of a LINGO-1·p75NTR·NgR ternary complex. These findings contradict models postulating functional LINGO-1·p75 NTR ·NgR complexes in the plasma membrane.