IRSp53 Promotes Postsynaptic Density Formation and Actin Filament Bundling

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2022 Jul 12

PMID 35819332

Authors

Zhe Feng

Suho Lee

Bowen Jia

Tao Jian

Eunjoon Kim

Mingjie Zhang

Affiliations

Soon will be listed here.

Abstract

IRSp53 (aka BAIAP2) is a scaffold protein that couples membranes with the cytoskeleton in actin-filled protrusions such as filopodia and lamellipodia. The protein is abundantly expressed in excitatory synapses and is essential for synapse development and synaptic plasticity, although with poorly understood mechanisms. Here we show that specific multivalent interactions between IRSp53 and its binding partners PSD-95 or Shank3 drive phase separation of the complexes in solution. IRSp53 can be enriched to the reconstituted excitatory PSD (ePSD) condensates via bridging to the core and deeper layers of ePSD. Overexpression of a mutant defective in the IRSp53/PSD-95 interaction perturbs synaptic enrichment of IRSp53 in mouse cortical neurons. The reconstituted PSD condensates promote bundled actin filament formation both in solution and on membranes, via IRSp53-mediated actin binding and bundling. Overexpression of mutants that perturb IRSp53-actin interaction leads to defects in synaptic maturation of cortical neurons. Together, our studies provide potential mechanistic insights into the physiological roles of IRSp53 in synapse formation and function.

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References

Chung W, Choi S, Lee E, Park H, Kang J, Park H . Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression. Nat Neurosci. 2015; 18(3):435-43. DOI: 10.1038/nn.3927. View

Scita G, Confalonieri S, Lappalainen P, Suetsugu S . IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions. Trends Cell Biol. 2008; 18(2):52-60. DOI: 10.1016/j.tcb.2007.12.002. View

Goh W, Lim K, Sudhaharan T, Sem K, Bu W, Chou A . mDia1 and WAVE2 proteins interact directly with IRSp53 in filopodia and are involved in filopodium formation. J Biol Chem. 2011; 287(7):4702-14. PMC: 3281667. DOI: 10.1074/jbc.M111.305102. View

Cohen R, Blomberg F, Berzins K, Siekevitz P . The structure of postsynaptic densities isolated from dog cerebral cortex. I. Overall morphology and protein composition. J Cell Biol. 1977; 74(1):181-203. PMC: 2109867. DOI: 10.1083/jcb.74.1.181. View

Nair D, Hosy E, Petersen J, Constals A, Giannone G, Choquet D . Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J Neurosci. 2013; 33(32):13204-24. PMC: 6619720. DOI: 10.1523/JNEUROSCI.2381-12.2013. View

Bockmann J, Kreutz M, Gundelfinger E, Bockers T . ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53. J Neurochem. 2002; 83(4):1013-7. DOI: 10.1046/j.1471-4159.2002.01204.x. View

Nishiyama J, Yasuda R . Biochemical Computation for Spine Structural Plasticity. Neuron. 2015; 87(1):63-75. PMC: 4722820. DOI: 10.1016/j.neuron.2015.05.043. View

Lee S, Salazar S, Cox T, Strittmatter S . Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss. J Neurosci. 2019; 39(10):1910-1929. PMC: 6407289. DOI: 10.1523/JNEUROSCI.2983-18.2018. View

Kim M, Choi J, Yang J, Chung W, Kim J, Paik S . Enhanced NMDA receptor-mediated synaptic transmission, enhanced long-term potentiation, and impaired learning and memory in mice lacking IRSp53. J Neurosci. 2009; 29(5):1586-95. PMC: 6666077. DOI: 10.1523/JNEUROSCI.4306-08.2009. View

10.

McMahon H, Boucrot E . Membrane curvature at a glance. J Cell Sci. 2015; 128(6):1065-70. PMC: 4359918. DOI: 10.1242/jcs.114454. View

11.

Funato Y, Terabayashi T, Suenaga N, Seiki M, Takenawa T, Miki H . IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer Res. 2004; 64(15):5237-44. DOI: 10.1158/0008-5472.CAN-04-0327. View

12.

MacGillavry H, Song Y, Raghavachari S, Blanpied T . Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron. 2013; 78(4):615-22. PMC: 3668352. DOI: 10.1016/j.neuron.2013.03.009. View

13.

Lu Q, Ye F, Wei Z, Wen Z, Zhang M . Antiparallel coiled-coil-mediated dimerization of myosin X. Proc Natl Acad Sci U S A. 2012; 109(43):17388-93. PMC: 3491486. DOI: 10.1073/pnas.1208642109. View

14.

Zeng M, Diaz-Alonso J, Ye F, Chen X, Xu J, Ji Z . Phase Separation-Mediated TARP/MAGUK Complex Condensation and AMPA Receptor Synaptic Transmission. Neuron. 2019; 104(3):529-543.e6. PMC: 6842113. DOI: 10.1016/j.neuron.2019.08.001. View

15.

Liu P, Jong T, Maa M, Leu T . The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation. Oncogene. 2010; 29(27):3977-89. DOI: 10.1038/onc.2010.144. View

16.

Triller A, Choquet D . New concepts in synaptic biology derived from single-molecule imaging. Neuron. 2008; 59(3):359-74. DOI: 10.1016/j.neuron.2008.06.022. View

17.

Burette A, Park H, Weinberg R . Postsynaptic distribution of IRSp53 in spiny excitatory and inhibitory neurons. J Comp Neurol. 2014; 522(9):2164-78. PMC: 3997599. DOI: 10.1002/cne.23526. View

18.

Soltau M, Berhorster K, Kindler S, Buck F, Richter D, Kreienkamp H . Insulin receptor substrate of 53 kDa links postsynaptic shank to PSD-95. J Neurochem. 2004; 90(3):659-65. DOI: 10.1111/j.1471-4159.2004.02523.x. View

19.

Prevost C, Zhao H, Manzi J, Lemichez E, Lappalainen P, Callan-Jones A . IRSp53 senses negative membrane curvature and phase separates along membrane tubules. Nat Commun. 2015; 6:8529. PMC: 4634128. DOI: 10.1038/ncomms9529. View

20.

Lowenthal M, Markey S, Dosemeci A . Quantitative mass spectrometry measurements reveal stoichiometry of principal postsynaptic density proteins. J Proteome Res. 2015; 14(6):2528-38. PMC: 5597335. DOI: 10.1021/acs.jproteome.5b00109. View