Homodimerization and isoform-specific heterodimerization of neuroligins.
Neuroligins are postsynaptic adhesion proteins involved in the establishment of functional synapses in the central nervous system. In rodents, four genes give rise to neuroligins that function at distinct synapses, with corresponding neurotransmitter and subtype specificities. In the present study, we examined the interactions between the different neuroligins by isolating endogenous oligomeric complexes using in situ cross-linking on primary neurons. Examining hippocampal, striatal, cerebellar and spinal cord cultures, we found that neuroligins form constitutive dimers, including homomers and, most notably, neuroligin 1/3 heteromers. Additionally, we found that neuroligin monomers are specifically retained in the secretory pathway through a cellular quality control mechanism that involves the neuroligin transmembrane domain, ensuring that dimerization occurs prior to cell surface trafficking. Lastly, we identified differences in the dimerization capacity of autism-associated neuroligin mutants, and found that neuroligin 3 R471C mutants can form heterodimers with neuroligin 1. The pervasive nature of neuroligin dimerization indicates that the unit of neuroligin function is the dimer, and raises intriguing possibilities of distinct heterodimer functions, and of interactions between native and mutant neuroligins contributing to disease phenotypes.
Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, and DFG Center for the Molecular Physiology of the Brain, D-37075 Göttingen, Germany.
Alexandros
A
Poulopoulos
Tolga
T
Soykan
Liam P
LP
Tuffy
Matthieu
M
Hammer
Frédérique
F
Varoqueaux
Nils
N
Brose
D019943:Amino Acid Substitution; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000196:embryology; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000737:chemistry; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology
D015816:Cell Adhesion Molecules, Neuronal; D003432:Cross-Linking Reagents; D008565:Membrane Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C093438:neuroligin 1; C098004:neuroligin 3