title: Intramolecular regulation of presynaptic scaffold protein SYD-2/liprin-α.
abstract: SYD-2/liprin-α is a multi-domain protein that associates with and recruits multiple active zone molecules to form presynaptic specializations. Given SYD-2's critical role in synapse formation, its synaptogenic ability is likely tightly regulated. However, mechanisms that regulate SYD-2 function are poorly understood. In this study, we provide evidence that SYD-2's function may be regulated by interactions between its coiled-coil (CC) domains and sterile α-motif (SAM) domains. We show that the N-terminal CC domains are necessary and sufficient to assemble functional synapses while C-terminal SAM domains are not, suggesting that the CC domains are responsible for the synaptogenic activity of SYD-2. Surprisingly, syd-2 alleles with single amino acid mutations in the SAM domain show strong loss of function phenotypes, suggesting that SAM domains also play an important role in SYD-2's function. A previously characterized syd-2 gain-of-function mutation within the CC domains is epistatic to the loss-of-function mutations in the SAM domain. In addition, yeast two-hybrid analysis showed interactions between the CC and SAM domains. Thus, the data is consistent with a model where the SAM domains regulate the CC domain-dependent synaptogenic activity of SYD-2. Taken together, our study provides new mechanistic insights into how SYD-2's activity may be modulated to regulate synapse formation during development.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Stanford University, 385 Serra Mall, Stanford, CA 94305, United States; Neurosciences Program, Stanford University, 385 Serra Mall, Stanford, CA 94305, United States.
authors.forename: Poh Hui
authors.initials: PH
authors.lastname: Chia
authors.forename: Maulik R
authors.initials: MR
authors.lastname: Patel
authors.forename: Oliver I
authors.initials: OI
authors.lastname: Wagner
authors.forename: Dieter R
authors.initials: DR
authors.lastname: Klopfenstein
authors.forename: Kang
authors.initials: K
authors.lastname: Shen
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D020125:Mutation, Missense; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013569:Synapses / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C490598:SYD-2 protein, C elegans
keywords: Liprin-α; Negative regulation; SYD-2; Structure–function; Synapse formation
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