Characterization of a novel interaction between the AMPA receptor binding protein ABP and the membrane type 5 matrix metalloproteinase MT5-MMP

Matrix metalloproteinases (MMP) have been proposed to remodel the extracellular environment of neurons. Here I report that the metalloproteinase MT5-MMP (Membrane-Type 5 Matrix Metalloproteinase) binds to ABP (AMPA Receptor Binding Protein) and GRIP (Glutamate Receptor Interaction Protein), two related post-synaptic density (PSD) PDZ domain proteins that target AMPA receptors to synapses. The MT5-MMP C-terminus binds ABP PDZ5 and the two proteins co-immunoprecipitated and co-localized in heterologous cells. MT5-MMP localized in filopodia at the tips of growth cones in young (2-5 DIV) cultured embryonic hippocampal neurons, and at synapses in mature (21 DIV) neurons.; Its enrichment insynaptosomes also indicated a synaptic localization in mature brain. Deletion of the PDZ binding site impaired membrane trafficking of MT5-MMP, while exogenous ABP splice forms that are associated either with the plasma membrane or with the cytosol respectively co-localized with MT5-MMP in synaptic spines, or recruited MT5-MMP to intracellular compartments. I show that endogenous MT5-MMP is found in cultured neurons and brain lysates in a pro-enzyme form that is activated by furin and degraded by auto proteolysis. I also identify cadherins as MT5-MMP substrates. These results suggest that ABP directs MT5-MMP proteolytic activity to growth cones and synaptic sites in neurons, where it may regulate axon pathfinding or synapse remodeling through proteolysis of cadherins or other ECM or cell adhesion molecules.