title: Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation.
abstract: Neurotransmission is ensured by a high concentration of neurotransmitter receptors at the postsynaptic membrane. This is mediated by scaffold proteins that bridge the receptors with cytoskeleton. One such protein is rapsyn (receptor-associated protein at synapse), which is essential for acetylcholine receptor (AChR) clustering and NMJ (neuromuscular junction) formation. We show that the RING domain of rapsyn contains E3 ligase activity. Mutation of the RING domain that abolishes the enzyme activity inhibits rapsyn- as well as agrin-induced AChR clustering in heterologous and muscle cells. Further biological and genetic studies support a working model where rapsyn, a classic scaffold protein, serves as an E3 ligase to induce AChR clustering and NMJ formation, possibly by regulation of AChR neddylation. This study identifies a previously unappreciated enzymatic function of rapsyn and a role of neddylation in synapse formation, and reveals a potential target of therapeutic intervention for relevant neurological disorders.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Xing
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Chengyong
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Arnab
authors.initials: A
authors.lastname: Barik
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhi
authors.affiliation: Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30912, USA. Electronic address: lmei@augusta.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D018171:Agrin / Q000378:metabolism*; D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018171:Agrin; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K; D044767:Ubiquitin-Protein Ligases
keywords: AChR; E3 ligase; RING domain; neddylation; rapsyn