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The Journal of Neuroscience, December 20, 2006, 26(51):13202-13212; doi:10.1523/JNEUROSCI.4608-06.2006

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Cellular/Molecular
Connecdenn, A Novel DENN Domain-Containing Protein of Neuronal Clathrin-Coated Vesicles Functioning in Synaptic Vesicle Endocytosis

Patrick D. Allaire,¹ Brigitte Ritter,¹ Sebastien Thomas,¹ Jonathon L. Burman,¹ Alexei Yu. Denisov,² Valerie Legendre-Guillemin,¹ Scott Q. Harper,³ Beverly L. Davidson,³ Kalle Gehring,² and Peter S. McPherson¹

¹Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, H3A 2B4, ²Department of Biochemistry and Montreal Joint Centre for Structural Biology, McGill University, Montreal, Quebec, Canada, H3G 1Y6, and ³Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242

Correspondence should be addressed to Dr. Peter S. McPherson, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. Email: peter.mcpherson{at}mcgill.ca

Clathrin-coated vesicles (CCVs) are responsible for the endocytosis of multiple cargo, including synaptic vesicle membranes. We now describe a new CCV protein, termed connecdenn, that contains an N-terminal DENN (differentially expressed in neoplastic versus normal cells) domain, a poorly characterized protein module found in multiple proteins of unrelated function and a C-terminal peptide motif domain harboring three distinct motifs for binding the -ear of the clathrin adaptor protein 2 (AP-2). Connecdenn coimmunoprecipitates and partially colocalizes with AP-2, and nuclear magnetic resonance and peptide competition studies reveal that all three -ear-binding motifs contribute to AP-2 interactions. In addition, connecdenn contains multiple Src homology 3 (SH3) domain-binding motifs and coimmunoprecipitates with the synaptic SH3 domain proteins intersectin and endophilin A1. Interestingly, connecdenn is enriched on neuronal CCVs and is present in the presynaptic compartment of neurons. Moreover, connecdenn has a uniquely stable association with CCV membranes because it resists extraction with Tris and high-salt buffers, unlike most other CCV proteins, but it is not detected on purified synaptic vesicles. Together, these observations suggest that connecdenn functions on the endocytic limb of the synaptic vesicle cycle. Accordingly, disruption of connecdenn interactions with its binding partners through overexpression of the C-terminal peptide motif domain or knock down of connecdenn through lentiviral delivery of small hairpin RNA both lead to defects in synaptic vesicle endocytosis in cultured hippocampal neurons. Thus, we identified connecdenn as a component of the endocytic machinery functioning in synaptic vesicle endocytosis, providing the first evidence of a role for a DENN domain-containing protein in endocytosis.

Key words: AP-2; clathrin; DENN domains; endocytosis; endophilin; intersectin; NMR; synaptic vesicle

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Received Nov. 23, 2005; revised Nov. 7, 2006; accepted Nov. 7, 2006.

Correspondence should be addressed to Dr. Peter S. McPherson, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. Email: peter.mcpherson{at}mcgill.ca

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