Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions.
The heterophilic synaptic adhesion molecules neuroligins and neurexins are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca2+-dependent and regulated by alternative splicing. We report a structure of the complex at a resolution of 2.4 A between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin-1beta (NX1beta) LNS (laminin, neurexin and sex hormone-binding globulin-like) domain. The structure revealed a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca2+-mediated and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data supported a mechanism wherein splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1beta interface. Mapping neuroligin mutations implicated in autism indicated that most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.
Chen
Xiaoyan
X
Northwestern University Feinberg School of Medicine, Department of Molecular Pharmacology & Biological Chemistry, Searle 8-417, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
Liu
Heli
H
Shim
Ann H R
AH
Focia
Pamela J
PJ
He
Xiaolin
X
D017398:Alternative Splicing; D001321:Autistic Disorder / Q000235:genetics*; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000502:physiology; D015816:Cell Adhesion Molecules, Neuronal; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry* / Q000502:physiology; D011487:Protein Conformation; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; C093438:neuroligin 1; C086959:neurexin Ibeta; D002118:Calcium