Interaction of the ERC Family of RIM-binding Proteins with the Liprin-α Family of Multidomain Proteins

Ko, Jaewon; Na, Moonseok; Kim, Se‐Ho; Lee, Jae-Ran; Kim, Eunjoon

doi:10.1074/jbc.m307561200

Cited by 174 publications

(197 citation statements)

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“…Although the Liprin-␣ protein contains no predicted catalytic domains, human Liprin-␣1 has been shown to undergo autophosphorylation (31), suggesting that it might act as a kinase. Alternatively, Liprin-␣ might promote the association of LAR with its substrates; mammalian Liprin-␣ family members have been shown to bind to a variety of synaptic molecules (21,22,32). Although the LAR substrate Ena binds directly to the intracellular domain of LAR (17), the Drosophila Trio homologue lacks the domains that mediate LAR binding by human Trio (15) and might require an adaptor protein such as Liprin-␣.…”

Section: Discussionmentioning

confidence: 99%

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Hofmeyer

Maurel-Zaffran

Sink

et al. 2006

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

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In the Drosophila visual system, the color-sensing photoreceptors R7 and R8 project their axons to two distinct layers in the medulla. Loss of the receptor tyrosine phosphatase LAR from R7 photoreceptors causes their axons to terminate prematurely in the R8 layer. Here we identify a null mutation in the Liprin-␣ gene based on a similar R7 projection defect. Liprin-␣ physically interacts with the inactive D2 phosphatase domain of LAR, and this domain is also essential for R7 targeting. However, another LAR-dependent function, egg elongation, requires neither Liprin-␣ nor the LAR D2 domain. Although human and Caenorhabditis elegans Liprin-␣ proteins have been reported to control the localization of LAR, we find that LAR localizes to focal adhesions in Drosophila S2R؉ cells and to photoreceptor growth cones in vivo independently of Liprin-␣. In addition, Liprin-␣ overexpression or loss of function can affect R7 targeting in the complete absence of LAR. We conclude that Liprin-␣ does not simply act by regulating LAR localization but also has LAR-independent functions. receptor tyrosine phosphatase ͉ visual system ͉ Drosophila T he color-sensitive photoreceptors of the Drosophila visual system, R7 and R8, provide a simple system in which to study layer-specific axon targeting. Whereas the outer photoreceptors R1-R6 project their axons to the lamina, R7 and R8 project to the medulla, where R8 terminates in the more superficial M3 layer and R7 in the deeper M6 layer. This targeting occurs in two stages, with both R7 and R8 growth cones pausing in separate temporary layers before proceeding to their final positions (1). Several genes are known to contribute to the establishment of the R7 and R8 projection pattern. The transcription factor Runt is expressed in R7 and R8, and its misexpression is sufficient to target R2 and R5 to the medulla, suggesting that it controls the choice of optic neuropil (2). Endogenous expression of the homophilic cell adhesion molecule Capricious (Caps) in R8 or its ectopic expression in R7 directs these photoreceptors to terminate in the Caps-positive M3 layer (3). The transmembrane cadherin Flamingo (Fmi) is required for R8 targeting (4, 5), whereas loss of either N-cadherin (Ncad) (6) or one of the receptor protein tyrosine phosphatases (RPTPs), PTP69D (7) or LAR (8, 9), causes R7 to terminate inappropriately in the R8 layer.Other functions of LAR include axonal patterning of photoreceptors R1-R6 (9) and embryonic motor neurons (10, 11), synapse morphogenesis at the larval neuromuscular junction (NMJ) (12), and polarization of actin filaments in the follicle cells surrounding the oocyte, which promotes egg elongation along the anterior-posterior axis (13,14). It is unclear how LAR and other RPTPs signal within the cell to induce the cytoskeletal rearrangements that mediate these functions. Trio, a guanine nucleotide exchange factor for Rac (15), and Enabled (Ena), which regulates actin polymerization (16), show genetic interactions with LAR in both R7 targeting (8) and motor axon guidance ...

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Section: Discussionmentioning

confidence: 99%

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Hofmeyer

Maurel-Zaffran

Sink

et al. 2006

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

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“…The interaction between Munc13-NT and Rim-ZF, for example, is important but not exclusively responsible for the active zone recruitment of Munc13 (Andrews-Zwilling et al, 2006). Interactions with additional multivalent scaffolding proteins such as those of Rim and CAST1 with liprin-␣ (Schoch et al, 2002;Ko et al, 2003;, of CAST1 with syntenin-1 (Ko et al, 2006), of Munc13 with ␤-spectrin (Sakaguchi et al, 1998), and of Aczonin with GIT1 add additional layers of complexity to the molecular architecture of the active zone and to the formation of a polymeric, highly interconnected protein lattice. Hence, the "targeting code" of active zone proteins is probably combinatorial, and, through their early association along the secretory pathway, they can find the way to synaptic terminals as fellow travelers, although each of them may possess only part of the targeting information.…”

Section: Involvement Of Interacting Domains In Synaptogenesis and Synmentioning

confidence: 99%

A Protein Interaction Node at the Neurotransmitter Release Site: Domains of Aczonin/Piccolo, Bassoon, CAST, and Rim Converge on the N-Terminal Domain of Munc13-1

Wang

Hu²,

Zięba³

et al. 2009

J. Neurosci.

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Multidomain scaffolding proteins organize the molecular machinery of neurotransmitter vesicle dynamics during synaptogenesis and synaptic activity. We find that domains of five active zone proteins converge on an interaction node that centers on the N-terminal region of Munc13-1 and includes the zinc-finger domain of Rim1, the C-terminal region of Bassoon, a segment of CAST1/ELKS2, and the third coiled-coil domain (CC3) of either Aczonin/Piccolo or Bassoon. This multidomain complex may constitute a center for the physical and functional integration of the protein machinery at the active zone. An additional connection between Aczonin and Bassoon is mediated by the second coiled-coil domain of Aczonin. Recombinant Aczonin-CC3, expressed in cultured neurons as a green fluorescent protein fusion protein, is targeted to synapses and suppresses vesicle turnover, suggesting involvements in synaptic assembly as well as activity. Our findings show that Aczonin, Bassoon, CAST1, Munc13, and Rim are closely and multiply interconnected, they indicate that Aczonin-CC3 can actively participate in neurotransmitter vesicle dynamics, and they highlight the N-terminal region of Munc13-1 as a hub of protein interactions by adding three new binding partners to its mechanistic potential in the control of synaptic vesicle priming.

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“…Therefore, SYD-1 and SYD-2 (liprin-α) are necessary for clustering synaptic vesicles and vesicle-associated proteins at presynaptic sites as well as for the assembly of active zone components. Given that the vertebrate homolog of SYD-2, liprin-α, directly interacts with ERC (ELKS-1) and GIT, it is possible that SYD-2 clusters these components to synapses in HSNL by direct binding 33,34 . …”

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confidence: 99%

Hierarchical assembly of presynaptic components in defined C. elegans synapses

et al. 2006

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The presynaptic regions of axons accumulate synaptic vesicles, active zone proteins and periactive zone proteins. However, the rules for orderly recruitment of presynaptic components are not well understood. We systematically examined molecular mechanisms of presynaptic development in egg-laying synapses of Caenorhabditis elegans, demonstrating that two scaffolding molecules, SYD-1 and SYD-2, have key roles in presynaptic assembly. SYD-2 (liprin-α) was previously shown to regulate the size and the shape of active zones. We now show that in syd-1 and syd-2 mutants, synaptic vesicles and numerous other presynaptic proteins fail to accumulate at presynaptic sites. SYD-1 and SYD-2 function cell-autonomously at presynaptic terminals, downstream of synaptic specificity molecule SYG-1. SYD-1 is likely to act upstream of SYD-2 to positively regulate its synaptic assembly activity. These data imply a hierarchical organization of presynaptic assembly, in which transmembrane specificity molecules initiate synaptogenesis by recruiting a few key scaffolding proteins, which in turn assemble other presynaptic components.Cellular and molecular processes during synapse formation and maturation dictate specificity and types and strength of synaptic connections between neurons, ultimately determining the functional properties of neural circuits. It is believed that synapse formation is triggered by contact between synaptic partners, which induces the transformation of a patch of unspecialized plasma membrane of the presynaptic neuron into a presynaptic apparatus. Presynaptic sites are structurally characterized by a pool of synaptic vesicles and active zones, where synaptic vesicles undergo exocytosis 1 . Functionally, neurotransmitter Author Contributions: M.R.P. and K.S. designed the experiments, analyzed the data and wrote the paper. M.R.P, E.K.L. and V.Y.P performed the experiments. J.G.C. and C.I.B. designed the ASI synapse screen. J.G.C. isolated syd-2(ky292) and M.Z. contributed the GFP::SYD-2 construct. Competing Interests Statement:The authors declare that they have no competing financial interests. release is a multistep process, which involves coordinated actions of many presynaptic proteins. How various molecular components are organized into such complex machinery during development is an unresolved question. NIH Public AccessA number of membrane molecules have been implicated in synapse development. Transmembrane molecules are attractive candidates for initiating presynaptic differentiation when an axon comes in contact with a potential postsynaptic target 2 . For example, postsynaptically expressed neuroligin is capable of clustering β-neurexin in the presynaptic neuron, which then causes accumulation of synaptic vesicles 3,4 . Similarly, synCAM, another homophilic trans-membrane protein, can initiate presynaptic assembly in vitro 5 . Other transmembrane proteins have a role in patterning synapses although they are not required for synapse formation per se. The immunoglobulin superfamily (IgSF) proteins Sdk-...

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Interaction of the ERC Family of RIM-binding Proteins with the Liprin-α Family of Multidomain Proteins

Cited by 174 publications

References 36 publications

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

A Protein Interaction Node at the Neurotransmitter Release Site: Domains of Aczonin/Piccolo, Bassoon, CAST, and Rim Converge on the N-Terminal Domain of Munc13-1

Hierarchical assembly of presynaptic components in defined C. elegans synapses

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