LINGO-1 Protein Interacts with the p75 Neurotrophin Receptor in Intracellular Membrane Compartments *

Background: LINGO-1·p75 NTR ·NgR complexes at the cell surface are believed to mediate responses to myelin inhibitors of axon growth. Results: LINGO-1 is intracellular and competes with NgR for binding to p75 NTR. Conclusion: The existence of cell-surface ternary complexes of p75 NTR, NgR, and LINGO-1 cannot be confirmed. Significance: The commonly accepted mechanism for p75 NTR -mediated responses of axons to inhibitory myelin proteins is untenable. 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 plasma membrane expression. p75 NTR associated predominantly with natively expressed LINGO-1 containing immature N -glycans, characteristic of protein that has not completed trans -Golgi-mediated 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·p75 NTR ·NgR ternary complex. These findings contradict models postulating functional LINGO-1·p75 NTR ·NgR complexes in the plasma membrane.