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Mechanisms controlling membrane recruitment and activation of autoinhibited SHIP1

Grace L. Waddell, Emma E. Drew, Henry P. Rupp, Scott D. Hansen
doi: https://doi.org/10.1101/2023.04.30.538895
Grace L. Waddell
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403
2Institute of Molecular Biology, University of Oregon, Eugene, OR 97403
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Emma E. Drew
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403
2Institute of Molecular Biology, University of Oregon, Eugene, OR 97403
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Henry P. Rupp
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403
2Institute of Molecular Biology, University of Oregon, Eugene, OR 97403
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Scott D. Hansen
1Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403
2Institute of Molecular Biology, University of Oregon, Eugene, OR 97403
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  • For correspondence: shansen5@uoregon.edu
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Abstract

Signal transduction downstream of growth factor and immune receptor activation relies on the production of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P3) lipids by phosphoinositide-3-kinase (PI3K). Regulating the strength and duration of PI3K signaling in immune cells, Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) controls the dephosphorylation of PI(3,4,5)P3 to generate PI(3,4)P2. Although SHIP1 has been shown to regulate neutrophil chemotaxis, B-cell signaling, and cortical oscillations in mast cells, the role that lipid and protein interactions serve in controlling SHIP1 membrane recruitment and activity remains unclear. Using single molecule TIRF microscopy, we directly visualized membrane recruitment and activation of SHIP1 on supported lipid bilayers and the cellular plasma membrane. We find that SHIP1’s interactions with lipids are insensitive to dynamic changes in PI(3,4,5)P3 both in vitro and in vivo. Very transient SHIP1 membrane interactions were detected only when membranes contained a combination of phosphatidylserine (PS) and PI(3,4,5)P3 lipids. Molecular dissection reveals that SHIP1 is autoinhibited with the N-terminal SH2 domain playing a critical role in suppressing phosphatase activity. Robust SHIP1 membrane localization and relief of autoinhibition can be achieved through interactions with immunoreceptor derived phosphopeptides presented either in solution or conjugated to supported membranes. Overall, this work provides new mechanistic details concerning the dynamic interplay between lipid binding specificity, protein-protein interactions, and activation of autoinhibited SHIP1.

Competing Interest Statement

The authors have declared no competing interest.

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Posted May 01, 2023.
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Mechanisms controlling membrane recruitment and activation of autoinhibited SHIP1
Grace L. Waddell, Emma E. Drew, Henry P. Rupp, Scott D. Hansen
bioRxiv 2023.04.30.538895; doi: https://doi.org/10.1101/2023.04.30.538895
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Mechanisms controlling membrane recruitment and activation of autoinhibited SHIP1
Grace L. Waddell, Emma E. Drew, Henry P. Rupp, Scott D. Hansen
bioRxiv 2023.04.30.538895; doi: https://doi.org/10.1101/2023.04.30.538895

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