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Mechanism of IRSp53 inhibition by 14-3-3

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  • David J. Kast

    (University of Pennsylvania
    Washington University)

  • Roberto Dominguez

    (University of Pennsylvania)

Abstract

Filopodia are precursors of dendritic spines and polarized cell migration. The I-BAR-domain protein IRSp53 is a key regulator of filopodia dynamics that couples Rho-GTPase signaling to cytoskeleton and membrane remodeling, playing essential roles in neuronal development and cell motility. Here, we describe the structural-functional basis for 14-3-3-dependent inhibition of IRSp53. Phosphoproteomics, quantitative binding and crystallographic studies demonstrate that 14-3-3 binds to two pairs of phosphorylation sites in IRSp53. Using bicistronic expression, we obtain an IRSp53 heterodimer in which only one subunit is phosphorylated, and show that each subunit of IRSp53 independently binds one 14-3-3 dimer. A FRET-sensor assay using natively phosphorylated IRSp53 reveals opposite conformational changes upon binding of activatory (Cdc42, Eps8) or inhibitory (14-3-3) inputs. Finally, we show that 14-3-3 inhibits IRSp53 binding to membranes. Collectively, our findings support a mechanism whereby phosphorylation-dependent inhibition of IRSp53 by 14-3-3 counters membrane binding and interactions with Cdc42 and downstream cytoskeletal effectors.

Suggested Citation

  • David J. Kast & Roberto Dominguez, 2019. "Mechanism of IRSp53 inhibition by 14-3-3," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08317-8
    DOI: 10.1038/s41467-019-08317-8
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    Cited by:

    1. Michael J. Roy & Minglyanna G. Surudoi & Ashleigh Kropp & Jianmei Hou & Weiwen Dai & Joshua M. Hardy & Lung-Yu Liang & Thomas R. Cotton & Bernhard C. Lechtenberg & Toby A. Dite & Xiuquan Ma & Roger J., 2023. "Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Sara Bisi & Stefano Marchesi & Abrar Rizvi & Davide Carra & Galina V. Beznoussenko & Ines Ferrara & Gianluca Deflorian & Alexander Mironov & Giovanni Bertalot & Federica Pisati & Amanda Oldani & Angel, 2020. "IRSp53 controls plasma membrane shape and polarized transport at the nascent lumen in epithelial tubules," Nature Communications, Nature, vol. 11(1), pages 1-23, December.

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