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Connecdenn, a novel DENN domain-containing protein of neuronal clathrin-coated vesicles functioning in synaptic vesicle endocytosis

Allaire Patrick D., Ritter Brigitte, Thomas Sébastien, Burman Jonathon L., Denisov Alexei Yu, Legendre-Guillemin Valérie, Harper Scott Q., Davidson Beverly L., Gehring Kalle et McPherson Peter S.. (2006). Connecdenn, a novel DENN domain-containing protein of neuronal clathrin-coated vesicles functioning in synaptic vesicle endocytosis. Journal of Neuroscience, 26, (51), p. 13202-13212.

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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 α-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 α-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.

Type de document:Article publié dans une revue avec comité d'évaluation
Pages:p. 13202-13212
Version évaluée par les pairs:Oui
Sujets:Sciences de la santé > Sciences médicales > Biologie cellulaire
Sciences de la santé > Sciences médicales > Biologie moléculaire
Sciences de la santé > Sciences médicales > Neurosciences
Département, module, service et unité de recherche:Départements et modules > Département des sciences fondamentales
Mots-clés:AP-2, clathrin, DENN domains, endocytosis, endophilin, intersectin, NMR, synaptic vesicle
Déposé le:06 juin 2016 13:45
Dernière modification:05 déc. 2016 20:46
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