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Cited by 42Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancer

Structural basis for interdomain communication in SHIP2 providing high phosphatase activity

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Le Coq, Johanne, Camacho-Artacho, Marta, Velázquez, José Vicente, Santiveri, Clara M, Gallego, Luis Heredia, Campos-Olivas, Ramón, Dölker, Nicole, Lietha, Daniel·2017·eLife
DOI 10.7554/elife.26640PMC PMC5550278
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Abstract

SH2-containing-inositol-5-phosphatases (SHIPs) dephosphorylate the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) and play important roles in regulating the PI3K/Akt pathway in physiology and disease. Aiming to uncover interdomain regulatory mechanisms in SHIP2, we determined crystal structures containing the 5-phosphatase and a proximal region adopting a C2 fold. This reveals an extensive interface between the two domains, which results in significant structural changes in the phosphatase domain. Both the phosphatase and C2 domains bind phosphatidylserine lipids, which likely helps to position the active site towards its substrate. Although located distant to the active site, the C2 domain greatly enhances catalytic turnover. Employing molecular dynamics, mutagenesis and cell biology, we identify two distinct allosteric signaling pathways, emanating from hydrophobic or polar interdomain interactions, differentially affecting lipid chain or headgroup moieties of PI(3,4,5)P3. Together, this study reveals details of multilayered C2-mediated effects important for SHIP2 activity and points towards interesting new possibilities for therapeutic interventions.

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  • Upon binding to PI(3,4,5)P3, the 5' phosphatase catalytic domain phosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, which can bind to the C2 domain near the C-terminus.

    “Upon binding to PI(3,4,5)P3, the 5’ phosphatase catalytic domain phosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, which can bind to the C2 domain near the C-terminus [92, 107, 108].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [107]

    The Introduction states that SHIP dephosphorylates PI(3,4,5)P3 at the 5-position to generate PI(3,4)P2, contrary to the claim that it phosphorylates the substrate. The cited passages describe the C2 domain’s effects on catalysis and membrane binding, but do not establish that the product binds the C2 domain. (LLM, conf=0.88)

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  • SHIP1 binds to PI(3,4,5)P3 via its PH-L domain and dephosphorylates PI(3,4,5)P3 via its 5' phosphatase catalytic domain to generate PI(4,5)P2.

    “SHIP1 binds to PI(3,4,5)P3 via its PH-L domain and dephosphorylates PI(3,4,5)P3 via its 5’ phosphatase catalytic domain to generate PI(4,5)P2.”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [107]

    The Introduction (page not provided) says SHIP removes the 5-phosphate from PI(3,4,5)P3 to generate PI(3,4)P2, not the claimed PI(4,5)P2. It identifies a SHIP 5-phosphatase domain but does not establish the claimed PI(3,4,5)P3 binding through a SHIP1 PH-L domain. (LLM, conf=0.91)

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    Experimental — accuracy not yet measured

  • C2 domain of SHIP1 can bind to PI(4,5)P2, which is thought to allosterically regulate SHIP1's phosphatase activity.

    “C2 domain of SHIP1 can bind to PI(4,5)P2, which is thought to allosterically regulate SHIP1’s phosphatase activity.”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [107]

    The Introduction (page unavailable) says the SHIP1 C2 domain was reported to bind PI(3,4)P2, not PI(4,5)P2, and that this binding allosterically upregulates phosphatase activity. The claimed regulatory mechanism matches, but the named lipid does not. (LLM, conf=0.88)

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Cited by

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Authors
Le Coq, J., Camacho-Artacho, M., Velázquez, J. V., Santiveri, C. M., Gallego, L. H., Campos-Olivas, R., Dölker, N., & Lietha, D.
Affiliations
  • Cell Signalling and Adhesion Group, Spanish National Cancer Research Centre, Madrid, Spain
  • Spanish National Cancer Research Centre (ES)
  • Spectroscopy and Nuclear Magnetic Resonance Unit, Spanish National Cancer Research Centre, Madrid, Spain
Corresponding author
Lietha, Daniel
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2017-08-09
Volume
6
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.26640
PMC
PMC5550278
OpenAlex
W2744958234
Cited by
42
References
1
Citations by year
2026: 5 · 2025: 5 · 2024: 1 · 2023: 9 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 1
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministerio de Economía, Industria y Competitividad (BFU2010-15923, Project Retos BFU2016-77665-R)
  • Comunidad de Madrid (S2010/BMD-2457)
  • European Regional Development Fund (Project Retos BFU2016-77665-R)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
SHIP2, inter-domain communication, C2 domain, phosphatase activity, PI3K/Akt signaling, allosteric regulation, phosphatidylserine binding, crystal structure, molecular dynamics
MeSH terms
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Protein Domains, DNA Mutational Analysis, Humans, Models, Molecular, Phosphatidylserines, Protein Binding, Protein Conformation, Phosphatidylinositol Phosphates, Crystallography, X-Ray, Catalytic Domain, Molecular Dynamics Simulation

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