Structural and Biochemical Basis for the Inhibitory Effect of Liprin-α3 on Mouse Diaphanous 1 (mDia1) Function

Brenig, Julian; Boor, Susanne de; Knyphausen, Philipp; Kuhlmann, Nora; Wroblowski, Sarah; Baldus, Linda; Scislowski, Lukas; Artz, Oliver; Trauschies, P.; Baumann, Ulrich; Neundorf, Ines; Lammers, Michael

doi:10.1074/jbc.m114.621946

Cited by 7 publications

(6 citation statements)

References 64 publications

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“…7b). The predicted geometry of the tripartite IIa RPTP-Liprin-α-CASK complex is compatible to the idea that this complex can be further assembled into other important presynaptic proteins such as RIM 37 , mDia 42,43 , Liprinβ 22,45 , and GRIP1 53 . Such higher-order assembly of intracellular presynaptic proteins might be functionally and mechanistically linked to lateral alignments of transsynaptic connections via synaptic organizers 16,54 .…”

Section: Discussionsupporting

confidence: 78%

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Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α

et al. 2020

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Synapse formation is induced by transsynaptic interaction of neuronal cell-adhesion molecules termed synaptic organizers. Type IIa receptor protein tyrosine phosphatases (IIa RPTPs) function as presynaptic organizers. The cytoplasmic domain of IIa RPTPs consists of two phosphatase domains, and the membrane-distal one (D2) is essential for synapse formation. Liprin-α, which is an active zone protein critical for synapse formation, interacts with D2 via its C-terminal domain composed of three tandem sterile alpha motifs (tSAM). Structural mechanisms of this critical interaction for synapse formation remain elusive. Here, we report the crystal structure of the complex between mouse PTPδ D2 and Liprin-α3 tSAM at 1.91 Å resolution. PTPδ D2 interacts with the N-terminal helix and the first and second SAMs (SAM1 and SAM2, respectively) of Liprin-α3. Structure-based mutational analyses in vitro and in cellulo demonstrate that the interactions with Liprin-α SAM1 and SAM2 are essential for the binding and synaptogenic activity.

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Section: Discussionsupporting

confidence: 78%

“…1a). The N-terminal coiled-coil domain of Liprin-α mediates the binding to CAST/ELKS 39 , GIT1 40 , RIM 37 , KIF1A 41 , and mDia 42,43 . The tSAM domain of Liprin-α interacts with the D2 domain of IIa RPTPs 21,22 and CASK 44 .…”

mentioning

confidence: 99%

Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α

et al. 2020

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“…The LCR, only found in liprin-α3, folds as a short α-helix and interacts with mDia, an actin nucleator, to regulate the dynamics of actin filaments ( Sakamoto et al, 2012 ; Brenig et al, 2015 ). The structural study of the LCR/mDia complex showed that the LCR prevents mDia from adopting an auto-inhibited conformation ( Figure 4A ), therefore promoting actin polymerization in the cell ( Brenig et al, 2015 ). Although the LCR sequence is not conserved in other liprin-α proteins, liprin-α1 was found to interact with mDia ( Sakamoto et al, 2012 ).…”

Section: Other Protein-binding Regions In Liprin-αsmentioning

confidence: 99%

Liprin-α-Mediated Assemblies and Their Roles in Synapse Formation

Xie

Liang

et al. 2021

Front. Cell Dev. Biol.

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Brain’s functions, such as memory and learning, rely on synapses that are highly specialized cellular junctions connecting neurons. Functional synapses orchestrate the assembly of ion channels, receptors, enzymes, and scaffold proteins in both pre- and post-synapse. Liprin-α proteins are master scaffolds in synapses and coordinate various synaptic proteins to assemble large protein complexes. The functions of liprin-αs in synapse formation have been largely uncovered by genetic studies in diverse model systems. Recently, emerging structural and biochemical studies on liprin-α proteins and their binding partners begin to unveil the molecular basis of the synaptic assembly. This review summarizes the recent structural findings on liprin-αs, proposes the assembly mechanism of liprin-α-mediated complexes, and discusses the liprin-α-organized assemblies in the regulation of synapse formation and function.

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“…Although we propose that the activation of Diaphanous family formins is a two-step process, we do not envisage that indiscriminate protein binding to the DID necessarily confers a formin-activating function. For instance, the binding of Liprin-␣3 to the DID of DIAPH1 has an inhibitory effect, as it prevents the correct targeting of DIAPH1 to the membrane (21,22). Liprin-␣3 has been proposed to displace IQGAP1 from DIAPH1 (21), suggesting that the control of formin activity can occur through both positive and negative effectors, and providing yet greater scope for the multilayered regulation of the actin cytoskeleton.…”

Section: Iqgap1 Enhances Diaph1 Activitymentioning

confidence: 99%

“…For instance, the binding of Liprin-␣3 to the DID of DIAPH1 has an inhibitory effect, as it prevents the correct targeting of DIAPH1 to the membrane (21,22). Liprin-␣3 has been proposed to displace IQGAP1 from DIAPH1 (21), suggesting that the control of formin activity can occur through both positive and negative effectors, and providing yet greater scope for the multilayered regulation of the actin cytoskeleton.…”

Section: Iqgap1 Enhances Diaph1 Activitymentioning

confidence: 99%

The scaffold-protein IQGAP1 enhances and spatially restricts the actin-nucleating activity of Diaphanous-related formin 1 (DIAPH1)

Chen

Arora

Lai

et al. 2020

Journal of Biological Chemistry

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The actin cytoskeleton is a dynamic array of filaments that undergoes rapid remodeling to drive many cellular processes. An essential feature of filament remodeling is the spatio-temporal regulation of actin filament nucleation. One family of actin filament nucleators, the Diaphanous-related formins, is activated by the binding of small G-proteins such as RhoA. However, RhoA only partially activates formins, suggesting that additional factors are required to fully activate the formin. Here we identify one such factor, IQ motif containing GTPase activating protein-1 (IQGAP1), which enhances RhoA-mediated activation of the Diaphanous-related formin (DIAPH1) and targets DIAPH1 to the plasma membrane. We find that the inhibitory intramolecular interaction within DIAPH1 is disrupted by the sequential binding of RhoA and IQGAP1. Binding of RhoA and IQGAP1 robustly stimulates DIAPH1-mediated actin filament nucleation in vitro. In contrast, the actin capping protein Flightless-I, in conjunction with RhoA, only weakly stimulates DIAPH1 activity. IQGAP1, but not Flightless-I, is required to recruit DIAPH1 to the plasma membrane where actin filaments are generated. These results indicate that IQGAP1 enhances RhoA-mediated activation of DIAPH1 in vivo. Collectively these data support a model where the combined action of RhoA and an enhancer ensures the spatio-temporal regulation of actin nucleation to stimulate robust and localized actin filament production in vivo.

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Structural and Biochemical Basis for the Inhibitory Effect of Liprin-α3 on Mouse Diaphanous 1 (mDia1) Function

Cited by 7 publications

References 64 publications

Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α

Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α

Liprin-α-Mediated Assemblies and Their Roles in Synapse Formation

The scaffold-protein IQGAP1 enhances and spatially restricts the actin-nucleating activity of Diaphanous-related formin 1 (DIAPH1)

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