Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

Eun Suk Song; Hyeln Jang; Hou Fu Guo; Maria A. Juliano; Luiz Juliano; Andrew J. Morris; Emilia Galperin; David W. Rodgers; Louis B. Hersh

doi:10.1073/pnas.1613447114

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

Eun Suk Song, Hyeln Jang, Hou Fu Guo, Maria A. Juliano, Luiz Juliano, Andrew J. Morris, Emilia Galperin, David W. Rodgers, Louis B. Hersh

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily V_max. The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed. IDE binds PtdInsPs from solution, immobilized on membranes, or presented in liposomes. Interaction with PtdInsPs, likely PtdIns(3)P, plays a role in localizing IDE to endosomes, where the enzyme reportedly encounters physiological substrates. Thus, InsPs and PtdInsPs can serve as endogenous modulators of IDE activity, as well as regulators of its intracellular spatial distribution.

Original language	English
Pages (from-to)	E2826-E2835
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	14
DOIs	https://doi.org/10.1073/pnas.1613447114
State	Published - Apr 4 2017

Bibliographical note

Funding Information:
We thank Dr. A. Saiardi for providing the isomer of InsP7 used in this study and acknowledge the use of facilities at the University of Kentucky Center for Structural Biology and the Center for Molecular Medicine Protein Core (supported by National Institutes of Health Grant P20 GM103486). This work was supported by National Institutes of Health grants GM 11787 (to L.B.H.), NS38041 (to D.W.R.), GM113087 (to E.G.); American Cancer Society Grant RSG-14-172-01-CSM (to E.G.); American Heart Association Grant 15PRE25090207 (to H.J.); and National Science Foundation Grant IIA-1355438 (to D.W.R.). Part of this work was supported by the Fundação de Amparo à Pesquisado Estado de São Paulo (Project 12/50191-4R) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Projects 443978-2014-0 and 467478-2014-7).

Funding

We thank Dr. A. Saiardi for providing the isomer of InsP7 used in this study and acknowledge the use of facilities at the University of Kentucky Center for Structural Biology and the Center for Molecular Medicine Protein Core (supported by National Institutes of Health Grant P20 GM103486). This work was supported by National Institutes of Health grants GM 11787 (to L.B.H.), NS38041 (to D.W.R.), GM113087 (to E.G.); American Cancer Society Grant RSG-14-172-01-CSM (to E.G.); American Heart Association Grant 15PRE25090207 (to H.J.); and National Science Foundation Grant IIA-1355438 (to D.W.R.). Part of this work was supported by the Fundação de Amparo à Pesquisado Estado de São Paulo (Project 12/50191-4R) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Projects 443978-2014-0 and 467478-2014-7).

Funders	Funder number
Center for Molecular Medicine Protein Core
University of Kentucky Center for Structural Biology
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China	IIA-1355438
National Institutes of Health (NIH)	NS38041, P20 GM103486, GM113087, GM 11787
American Cancer Society-Michigan Cancer Research Fund	RSG-14-172-01-CSM
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	P20GM103527
American the American Heart Association	15PRE25090207
Fundação de Amparo à Pesquisa do Estado de São Paulo	12/50191-4R
Conselho Nacional de Desenvolvimento Científico e Tecnológico	443978-2014-0, 467478-2014-7

Keywords

Activation
Inositols
Insulin-degrading enzyme
Phosphatidylinositols
Subcellular localization

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.1613447114

Cite this

Song, E. S., Jang, H., Guo, H. F., Juliano, M. A., Juliano, L., Morris, A. J., Galperin, E., Rodgers, D. W., & Hersh, L. B. (2017). Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes. Proceedings of the National Academy of Sciences of the United States of America, 114(14), E2826-E2835. https://doi.org/10.1073/pnas.1613447114

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title = "Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes",

abstract = "Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily Vmax. The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed. IDE binds PtdInsPs from solution, immobilized on membranes, or presented in liposomes. Interaction with PtdInsPs, likely PtdIns(3)P, plays a role in localizing IDE to endosomes, where the enzyme reportedly encounters physiological substrates. Thus, InsPs and PtdInsPs can serve as endogenous modulators of IDE activity, as well as regulators of its intracellular spatial distribution.",

keywords = "Activation, Inositols, Insulin-degrading enzyme, Phosphatidylinositols, Subcellular localization",

author = "Song, \{Eun Suk\} and Hyeln Jang and Guo, \{Hou Fu\} and Juliano, \{Maria A.\} and Luiz Juliano and Morris, \{Andrew J.\} and Emilia Galperin and Rodgers, \{David W.\} and Hersh, \{Louis B.\}",

note = "Funding Information: We thank Dr. A. Saiardi for providing the isomer of InsP7 used in this study and acknowledge the use of facilities at the University of Kentucky Center for Structural Biology and the Center for Molecular Medicine Protein Core (supported by National Institutes of Health Grant P20 GM103486). This work was supported by National Institutes of Health grants GM 11787 (to L.B.H.), NS38041 (to D.W.R.), GM113087 (to E.G.); American Cancer Society Grant RSG-14-172-01-CSM (to E.G.); American Heart Association Grant 15PRE25090207 (to H.J.); and National Science Foundation Grant IIA-1355438 (to D.W.R.). Part of this work was supported by the Funda{\c c}{\~a}o de Amparo {\`a} Pesquisado Estado de S{\~a}o Paulo (Project 12/50191-4R) and the Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (Projects 443978-2014-0 and 467478-2014-7).",

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Song, ES, Jang, H, Guo, HF, Juliano, MA, Juliano, L, Morris, AJ, Galperin, E , Rodgers, DW & Hersh, LB 2017, 'Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 14, pp. E2826-E2835. https://doi.org/10.1073/pnas.1613447114

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes. / Song, Eun Suk; Jang, Hyeln; Guo, Hou Fu et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 14, 04.04.2017, p. E2826-E2835.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

AU - Song, Eun Suk

AU - Jang, Hyeln

AU - Guo, Hou Fu

AU - Juliano, Maria A.

AU - Juliano, Luiz

AU - Morris, Andrew J.

AU - Galperin, Emilia

AU - Rodgers, David W.

AU - Hersh, Louis B.

N1 - Funding Information: We thank Dr. A. Saiardi for providing the isomer of InsP7 used in this study and acknowledge the use of facilities at the University of Kentucky Center for Structural Biology and the Center for Molecular Medicine Protein Core (supported by National Institutes of Health Grant P20 GM103486). This work was supported by National Institutes of Health grants GM 11787 (to L.B.H.), NS38041 (to D.W.R.), GM113087 (to E.G.); American Cancer Society Grant RSG-14-172-01-CSM (to E.G.); American Heart Association Grant 15PRE25090207 (to H.J.); and National Science Foundation Grant IIA-1355438 (to D.W.R.). Part of this work was supported by the Fundação de Amparo à Pesquisado Estado de São Paulo (Project 12/50191-4R) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Projects 443978-2014-0 and 467478-2014-7).

PY - 2017/4/4

Y1 - 2017/4/4

N2 - Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily Vmax. The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed. IDE binds PtdInsPs from solution, immobilized on membranes, or presented in liposomes. Interaction with PtdInsPs, likely PtdIns(3)P, plays a role in localizing IDE to endosomes, where the enzyme reportedly encounters physiological substrates. Thus, InsPs and PtdInsPs can serve as endogenous modulators of IDE activity, as well as regulators of its intracellular spatial distribution.

AB - Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily Vmax. The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed. IDE binds PtdInsPs from solution, immobilized on membranes, or presented in liposomes. Interaction with PtdInsPs, likely PtdIns(3)P, plays a role in localizing IDE to endosomes, where the enzyme reportedly encounters physiological substrates. Thus, InsPs and PtdInsPs can serve as endogenous modulators of IDE activity, as well as regulators of its intracellular spatial distribution.

KW - Activation

KW - Inositols

KW - Insulin-degrading enzyme

KW - Phosphatidylinositols

KW - Subcellular localization

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Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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