Liprin-α proteins: scaffold molecules for synapse maturation

Spangler, Samantha A.; Hoogenraad, Casper C.

doi:10.1042/bst0351278

Cited by 103 publications

(104 citation statements)

References 48 publications

(75 reference statements)

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“…Notably, in the hierarchy of active zone assembly, genetic analysis in C. elegans has placed Syd-1 upstream of Syd-2 (Liprin-α), a protein linked to long-range transport of vesicular axonal cargo 27,28 . We previously found that Liprin-α localization was severely disturbed in Syd-1 mutants and proposed that Syd-1 might anchor clusters of Liprin-α 5 .…”

Section: Syd-1 Retains Liprin-a and Nrx-1 At Synapsesmentioning

confidence: 99%

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

et al. 2012

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Understanding the process of synapse assembly in molecular and cell-biological detail is a prerequisite for understanding neural circuit development and activity-mediated remodeling, and thus is important for unraveling learning and memory processes (structural plasticity) [1][2][3] . Functional chemical synapses are characterized by two apposed compartments that must be coestablished with high spatiotemporal precision: the presynaptic active zone, where regulated and rapid fusion of neurotransmitter-filled synaptic vesicles takes place, and the postsynaptic density (PSD), which embeds neurotransmitter receptors.Glutamatergic neuromuscular junction (NMJ) terminals of Drosophila larvae grow to meet the requirements of the growing muscle fibers, a process in which new synapses are continuously added 4 (where a synapse is defined as a single active zone opposed by a single PSD 1 ). In vivo imaging has shown that presynaptic Syd-1 and Liprin-α clusters initiate active zone formation 5 . On the postsynaptic side, initial PSD growth depends on incorporation of a glutamate receptor (GluR) containing the GluRIIA subunit. Later PSD maturation is marked by the incorporation of GluRIIB-containing receptor complexes 6 . Synapse assembly is concluded at presynaptic active zones by the incorporation of the active zone scaffold component Bruchpilot (BRP) 5 .Coordinating synapse assembly requires signaling across the synaptic cleft, which separates pre-from postsynaptic membranes. Transsynaptic cell adhesion molecules are obvious candidates for coupling active zone and PSD assembly. In vitro, the Neurexin-Neuroligin (Nrx-Nlg) complex can mediate the trans-synaptic signaling required for synapse assembly 7,8 . How this signaling axis integrates with the additional assembly machinery, however, has remained largely unclear.Here, we provide evidence of a dual role for Syd-1 in early assembly of NMJ synapses. It retains Liprin-α clusters at active zones and is important for clustering of presynaptic Nrx-1, likely through a direct and PDZ-domain-dependent interaction. Consequently, Syd-1 is also needed for clustering of postsynaptic Nlg1, which organizes postsynaptic assembly. Coincident action of Syd-1 with Nrx-1-Nlg1 appears to allow active zone scaffolds to pass through an initial, still fragile assembly phase. We suggest that binding between Syd-1 and Nrx-1-Nlg1 is a means to coordinate pre-with postsynaptic assembly. Our study shows an example of how coincident action of a presynaptic active zone scaffold protein and a trans-synaptic cell adhesion protein module can spatiotemporally orchestrate synapse assembly. RESULTSInitially described in cell culture systems (for a review, see ref. 9), interaction between mammalian presynaptic Nrx proteins and postsynaptic Nlg molecules was proposed to be important for proper synapse assembly. However, genetic ablation of three Nlg (Nlgn) genes in mice 10 does not result in a substantial structural phenotype, potentially reflecting a strong capacity for compensatory processes in vivo.Nonethe...

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Section: Syd-1 Retains Liprin-a and Nrx-1 At Synapsesmentioning

confidence: 99%

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

et al. 2012

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“…Other components of the same cortical assembly are the scaffolding proteins liprin-a1 and b1, a coiled-coil adaptor ELKS/ERC1, and the kinesin-4 KIF21A (Lansbergen et al, 2006;van der Vaart et al, 2013). Both liprins and ELKS are best known for their role in organizing presynaptic secretory sites (Hida and Ohtsuka, 2010;Spangler and Hoogenraad, 2007); in agreement with this function, ELKS is required for efficient constitutive exocytosis in HeLa cells (Grigoriev et al, 2007(Grigoriev et al, , 2011. LL5b, liprins and ELKS form micrometer-sized cortical patch-like structures, which will be termed here cortical microtubule stabilization complexes, or CMSCs.…”

Section: Introductionmentioning

confidence: 99%

Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions

Bouchet

Gough

Willige

et al. 2016

Preprint

108

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The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5b and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.

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“…At the presynaptic terminals, the interaction of liprinα with the active zone proteins RIM and ELKS/CAST enhances presynaptic assembly and neurotransmitter release (12,13). At the postsynaptic sites, liprinα regulates the synaptic targeting of AMPA-type glutamate receptors through its interaction with GRIP (6,14); likewise, it regulates the trafficking of the cadherin-catenin adhesion protein complex through its interaction with the LAR family of receptor protein tyrosine phosphatases (15). Nevertheless, the molecular control that regulates the function of liprinα remains unclear.…”

Section: Cdk5-dependent Phosphorylation Of Liprinα1 Mediates Neuronalmentioning

confidence: 99%

“…The liprinα family comprises abundant scaffold proteins that have been suggested as being critical for synapse organization through their interactions with multiple synaptic proteins (6). At the presynaptic terminals, the interaction of liprinα with the active zone proteins RIM and ELKS/CAST enhances presynaptic assembly and neurotransmitter release (12,13).…”

Section: Cdk5-dependent Phosphorylation Of Liprinα1 Mediates Neuronalmentioning

confidence: 99%

“…Scaffold proteins regulate the structure and functions of synapses through protein-protein interactions and the recruitment of different groups of synaptic proteins (6,7). In particular, PSD-95, the most abundant scaffold protein in the PSD, interacts with specific synaptic proteins through its multiple protein-interaction domains.…”

Section: Cdk5-dependent Phosphorylation Of Liprinα1 Mediates Neuronalmentioning

confidence: 99%

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Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

Huang

Lin

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.

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Liprin-α proteins: scaffold molecules for synapse maturation

Cited by 103 publications

References 48 publications

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions

Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

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