A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones

Siebert, Matthias; Böhme, Mathias A.; Driller, J.H.; Babikir, Husam; Mampell, Malou M.; Rey, Ulises; Ramesh, Niraja; Matkovic, Tanja; Holton, Nicole; Reddy-Alla, Suneel; Göttfert, Fabian; Kamin, Dirk; Quentin, Christine; Klinedinst, Susan; Andlauer, Till F. M.; Hell, Stefan W.; Collins, Catherine A.; Wahl, Markus C.; Loll, Bernhard; Sigrist, Stephan J.

doi:10.7554/elife.06935

Cited by 29 publications

(37 citation statements)

References 97 publications

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“…This study found that BRP and RIM-binding protein (RBP) can be co-transported[62]. Intriguingly, RBP and BRP transport could be uncoupled[62]. Indeed, our data supports such an idea and suggests the possibility that BRP could be transported via a distinct mechanism.…”

Section: Discussionsupporting

confidence: 69%

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

et al. 2017

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Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs) and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

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Section: Discussionsupporting

confidence: 69%

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

et al. 2017

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“…Because active kinesin-dependent protein transport is required for long-term homeostatic plasticity in gluRIIA Null mutants 27 , we asked whether BRP/RBP transport mechanisms might be employed for AZ remodeling. For this we investigated proteins involved in BRP/RBP transport by their mutation which causes abnormal BRP/RBP accumulation in the moto-neuronal axons, such as Atg1 (Unc-51) 28 , serine–arginine (SR) protein kinase at location 79D (Srpk79D; 29, 30 ), and App-like interacting protein (Aplip-1, Jip1 or JNK interacting protein in mammals), a selective RBP transport-adaptor 31 (Fig. 3a,b).…”

Section: Resultsmentioning

confidence: 99%

Rapid active zone remodeling consolidates presynaptic potentiation

Boehme

McCarthy

Grasskamp

et al. 2018

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1 Synaptic transmission is mediated by neurotransmitter release at presynaptic active zones (AZs) 2 followed by postsynaptic neurotransmitter detection. Plastic changes in transmission maintain 3 functionality during perturbations and enable memory formation. Postsynaptic plasticity targets 4 neurotransmitter receptors, but presynaptic plasticity mechanisms directly regulating the 5 neurotransmitter release apparatus remain largely enigmatic. Here we describe that AZs consist 6 of nano-modular release site units and identify a molecular sequence adding more modules 7 within minutes of plasticity induction. This requires cognate transport machinery and a discrete 8 subset of AZ scaffold proteins. Structural remodeling is not required for the immediate 9 potentiation of neurotransmitter release, but rather necessary to sustain this potentiation over 10 longer timescales. Finally, mutations in Unc13 that disrupt homeostatic plasticity at the 11 neuromuscular junction also impair shot-term memory when central neurons are targeted, 12 suggesting that both forms of plasticity operate via Unc13. Together, while immediate synaptic 13 potentiation capitalizes on available material, it triggers the coincident incorporation of modular 14 release sites to consolidate stable synapse function. 16Neurotransmitter-laden synaptic vesicles (SVs) release their content at presynaptic active zones 17 (AZs) in response to Ca 2+ influx through voltage gated channels that respond to action-potential 18 (AP) depolarization. Neurotransmitter binding to postsynaptic receptors subsequently leads to 19 their activation for synaptic transmission. Modulation of transmission strength is called synaptic 20 plasticity. Long-term forms of synaptic plasticity are major cellular substrates for learning, 21 memory, and behavioral adaptation 1, 2 . Mechanisms of long-term synaptic plasticity modify the 22 structure and function of the presynaptic terminal and/or the postsynaptic apparatus. AZs are 23 covered by complex scaffolds composed of a conserved set of extended structural proteins. 24 ELKS/Bruchpilot (BRP), RIM, and RIM-binding protein (RBP) functionally organize the 25 coupling between Ca 2+ -channels and release machinery by immobilizing the critical (M)Unc13 26 release factors in clusters close to presynaptic Ca 2+ -channels and thus generate SV release sites, 27 at both mammalian and Drosophila synapses 3-12 . Whether and how discrete AZ release sites and 28 the associated release machinery are reorganized during plastic changes remains unknown. 29 One crucial form of presynaptic plasticity is the homeostatic control of neurotransmitter 30 release. This process, referred to as presynaptic homeostatic potentiation (PHP), is observed in 31 organisms ranging from invertebrates to humans, but is perhaps best illustrated at the larval 32 neuromuscular junction (NMJ) of Drosophila melanogaster 13, 14 . Here, PHP requires the core 33 AZ-scaffolding proteins RIM, RBP and Fife 15-17 and physiologically coincides with the 34 upregulat...

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“…The backbone rmsd is 0. 53 A when they are overlaid using the backbone heavy atoms in folded regions (residues 559-609 of SNK1-SH3, residues 530-582 of SNK2-SH3, and residues 476-527 of SNK3-SH3) (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

Solution structures of the SH3 domains from Shank scaffold proteins and their interactions with Cav1.3 calcium channels

et al. 2018

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Shank proteins are abundant scaffold proteins in the postsynaptic density (PSD) region of brain synapses. Mutations in Shank proteins are associated with autism, schizophrenia, and Alzheimer's disease. To gain insights into Shank protein interactions at the PSD, we determined the solution structures of the src homology 3 (SH3) domains of all three mammalian Shank proteins. Our findings indicate that they have identical and typical SH3 folding motifs, but unusual target-binding pockets. An investigation into the interaction between the Shank SH3 domains and the proline-rich region of the Cav1.3 calcium channel revealed an atypical interaction in which the highly acidic specificity binding pocket of the SH3 domains binds to a Cav1.3 region containing a cluster of three Arg residues. Our study provides insights into Shank SH3-mediated interactions.

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A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones

Cited by 29 publications

References 97 publications

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

Rapid active zone remodeling consolidates presynaptic potentiation

Solution structures of the SH3 domains from Shank scaffold proteins and their interactions with Cav1.3 calcium channels

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