Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2.
Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca2+-dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3-A crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform- and synapse-specific functions.
Koehnke
Jesko
J
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
Jin
Xiangshu
X
Budreck
Elaine C
EC
Posy
Shoshana
S
Scheiffele
Peter
P
Honig
Barry
B
Shapiro
Lawrence
L
D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D015816:Cell Adhesion Molecules, Neuronal; D002460:Cell Line; D002802:Cholinesterases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D011487:Protein Conformation
D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C098003:neuroligin 2; D002802:Cholinesterases