Abstract
Neuronal pentraxin 1 (NP1), neuronal pentraxin 2 (NP2), and neuronal pentraxin receptor (NPR) are members of a new family of proteins identified through interaction with a presynaptic snake venom toxin taipoxin. We have proposed that these three neuronal pentraxins represent a novel neuronal uptake pathway that may function during synapse formation and remodeling. We have investigated the mutual interactions of these proteins by characterizing their enrichment on taipoxin affinity columns; by expressing NP1, NP2, and NPR singly and together in Chinese hamster ovary cells; and by generating mice that fail to express NP1. NP1 and NP2 are secreted, exist as higher order multimers (probably pentamers), and interact with taipoxin and taipoxin-associated calcium-binding protein 49 (TCBP49). NPR is expressed on the cell membrane and does not bind taipoxin or TCBP49 by itself, but it can form heteropentamers with NP1 and NP2 that can be released from cell membranes. This is the first demonstration of heteromultimerization of pentraxins and release of a pentraxin complex by proteolysis. These processes are likely to directly effect the localization and function of neuronal pentraxins in neuronal uptake or synapse formation and remodeling.
Highlights
Neuronal pentraxin 1 (NP1), neuronal pentraxin 2 (NP2), and neuronal pentraxin receptor (NPR) are members of a new family of proteins identified through interaction with a presynaptic snake venom toxin taipoxin
NP1, NP2, and NPR are all expressed in the hippocampus, as revealed by in situ hybridization (1, 3, 9), and primary cultures of rat hippocampal neurons are sensitive to taipoxin, as evidenced by the swelling of presynaptic terminals and the cell surface exposure of synaptic vesicle proteins (1)
We have previously identified NP1, NP2, NPR, and the six EF-hand, calcium-binding protein taipoxinassociated calcium-binding protein 49 (TCBP49) as taipoxin-binding proteins
Summary
NEURONAL PENTRAXIN (NP) RECEPTOR BINDS TO TAIPOXIN AND TAIPOXIN-ASSOCIATED CALCIUM-BINDING PROTEIN 49 VIA NP1 AND NP2*. We identified four novel proteins, NP1,1 NP2, NPR, and TCBP49, that bind to affinity columns of the presynaptic snake venom neurotoxin taipoxin (1– 4). The action of this toxin in blocking synaptic transmission and synaptic vesicle recycling led us to study the interactions between these taipoxin-binding proteins, their role in the action of taipoxin at synapses, and their potential role in general neuronal uptake. NP1, NP2, and NPR can all be isolated on taipoxin columns, NP1 and NP2 columns, and TCBP49 columns, suggesting that they interact in vivo (3) These interactions are likely to mediate aspects of taipoxin toxicity in neurons and are indicative of a normal neuronal pathway that may be involved in the uptake of extracellular material. We have generated mice that lack NP1 in order to confirm these interactions in vivo
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