γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion

Marilia Barros; William J. Houlihan; Chelsea J. Paresi; Chelsea J. Paresi; Matthew Brendel; Kevin D. Rynearson; Chang Wook Lee; Olga Prikhodko; Cristina Cregger; Geoffrey Chang; Steven L. Wagner; Steven L. Wagner; M. Lane Gilchrist; Yue Ming Li; Yue Ming Li

doi:10.1021/acs.langmuir.0c01178

γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion

Marilia Barros, William J. Houlihan, Chelsea J. Paresi, Chelsea J. Paresi, Matthew Brendel, Kevin D. Rynearson, Chang Wook Lee, Olga Prikhodko, Cristina Cregger, Geoffrey Chang, Steven L. Wagner, Steven L. Wagner, M. Lane Gilchrist, Yue Ming Li, Yue Ming Li

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

6 Scopus citations

Abstract

γ-Secretase is a multisubunit complex that catalyzes intramembranous cleavage of transmembrane proteins. The lipid environment forms membrane microdomains that serve as spatio-temporal platforms for proteins to function properly. Despite substantial advances in the regulation of γ-secretase, the effect of the local membrane lipid microenvironment on the regulation of γ-secretase is poorly understood. Here, we characterized and quantified the partitioning of γ-secretase and its substrates, the amyloid precursor protein (APP) and Notch, into lipid bilayers using solid-supported model membranes. Notch substrate is preferentially localized in the liquid-disordered (Ld) lipid domains, whereas APP and γ-secretase partition as single or higher complex in both phases but highly favor the ordered phase, especially after recruiting lipids from the ordered phase, indicating that the activity and specificity of γ-secretase against these two substrates are modulated by membrane lateral organization. Moreover, time-elapse measurements reveal that γ-secretase can recruit specific membrane components from the cholesterol-rich Lo phase and thus creates a favorable lipid environment for substrate recognition and therefore activity. This work offers insight into how γ-secretase and lipid modulate each other and control its activity and specificity.

Original language	English
Pages (from-to)	6569-6579
Number of pages	11
Journal	Langmuir
Volume	36
Issue number	23
DOIs	https://doi.org/10.1021/acs.langmuir.0c01178
State	Published - Jun 16 2020
Externally published	Yes

Funding

The authors acknowledge the National Institutes of Health and The National Science Foundation for the support of this research (NSF 1207480 and NIH S06GM008168-28 (M.L.G.), R01NS096275 (Y.-M.L.), RF1AG057593 (Y.-M.L.), U54CA137788/U54CA132378 (M.L.G. and Y.-M.L.), the JPB Foundation (Y.-M.L.), and The Cure Alzheimer’s Fund (S.L.W. and Y.-M.L.)). The authors also acknowledge William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of MSKCC, and the William Randolph Hearst Fund in Experimental Therapeutics.

Funders	Funder number
Commonwealth Foundation for Cancer Research
William Randolph Hearst Fund in Experimental Therapeutics
National Science Foundation	NSF 1207480
National Science Foundation
National Institutes of Health	RF1AG057593, U54CA137788/U54CA132378, R01NS096275
National Institutes of Health
National Institute of General Medical Sciences	S06GM008168
National Institute of General Medical Sciences
JPB Foundation
Cure Alzheimer's Fund

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10.1021/acs.langmuir.0c01178

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Barros, M., Houlihan, W. J., Paresi, C. J., Paresi, C. J., Brendel, M., Rynearson, K. D., Lee, C. W., Prikhodko, O., Cregger, C., Chang, G., Wagner, S. L., Wagner, S. L., Gilchrist, M. L., Li, Y. M., & Li, Y. M. (2020). γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion. Langmuir, 36(23), 6569-6579. https://doi.org/10.1021/acs.langmuir.0c01178

@article{dd749a173f6c40f0b4cd146eb2f2d13a,

title = "γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion",

abstract = "γ-Secretase is a multisubunit complex that catalyzes intramembranous cleavage of transmembrane proteins. The lipid environment forms membrane microdomains that serve as spatio-temporal platforms for proteins to function properly. Despite substantial advances in the regulation of γ-secretase, the effect of the local membrane lipid microenvironment on the regulation of γ-secretase is poorly understood. Here, we characterized and quantified the partitioning of γ-secretase and its substrates, the amyloid precursor protein (APP) and Notch, into lipid bilayers using solid-supported model membranes. Notch substrate is preferentially localized in the liquid-disordered (Ld) lipid domains, whereas APP and γ-secretase partition as single or higher complex in both phases but highly favor the ordered phase, especially after recruiting lipids from the ordered phase, indicating that the activity and specificity of γ-secretase against these two substrates are modulated by membrane lateral organization. Moreover, time-elapse measurements reveal that γ-secretase can recruit specific membrane components from the cholesterol-rich Lo phase and thus creates a favorable lipid environment for substrate recognition and therefore activity. This work offers insight into how γ-secretase and lipid modulate each other and control its activity and specificity.",

author = "Marilia Barros and Houlihan, {William J.} and Paresi, {Chelsea J.} and Paresi, {Chelsea J.} and Matthew Brendel and Rynearson, {Kevin D.} and Lee, {Chang Wook} and Olga Prikhodko and Cristina Cregger and Geoffrey Chang and Wagner, {Steven L.} and Wagner, {Steven L.} and Gilchrist, {M. Lane} and Li, {Yue Ming} and Li, {Yue Ming}",

note = "Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

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day = "16",

doi = "10.1021/acs.langmuir.0c01178",

language = "English",

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Barros, M, Houlihan, WJ, Paresi, CJ, Paresi, CJ, Brendel, M, Rynearson, KD, Lee, CW, Prikhodko, O, Cregger, C, Chang, G, Wagner, SL, Wagner, SL, Gilchrist, ML, Li, YM & Li, YM 2020, 'γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion', Langmuir, vol. 36, no. 23, pp. 6569-6579. https://doi.org/10.1021/acs.langmuir.0c01178

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T1 - γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion

AU - Barros, Marilia

AU - Houlihan, William J.

AU - Paresi, Chelsea J.

AU - Brendel, Matthew

AU - Rynearson, Kevin D.

AU - Lee, Chang Wook

AU - Prikhodko, Olga

AU - Cregger, Cristina

AU - Chang, Geoffrey

AU - Wagner, Steven L.

AU - Gilchrist, M. Lane

AU - Li, Yue Ming

PY - 2020/6/16

Y1 - 2020/6/16

N2 - γ-Secretase is a multisubunit complex that catalyzes intramembranous cleavage of transmembrane proteins. The lipid environment forms membrane microdomains that serve as spatio-temporal platforms for proteins to function properly. Despite substantial advances in the regulation of γ-secretase, the effect of the local membrane lipid microenvironment on the regulation of γ-secretase is poorly understood. Here, we characterized and quantified the partitioning of γ-secretase and its substrates, the amyloid precursor protein (APP) and Notch, into lipid bilayers using solid-supported model membranes. Notch substrate is preferentially localized in the liquid-disordered (Ld) lipid domains, whereas APP and γ-secretase partition as single or higher complex in both phases but highly favor the ordered phase, especially after recruiting lipids from the ordered phase, indicating that the activity and specificity of γ-secretase against these two substrates are modulated by membrane lateral organization. Moreover, time-elapse measurements reveal that γ-secretase can recruit specific membrane components from the cholesterol-rich Lo phase and thus creates a favorable lipid environment for substrate recognition and therefore activity. This work offers insight into how γ-secretase and lipid modulate each other and control its activity and specificity.

AB - γ-Secretase is a multisubunit complex that catalyzes intramembranous cleavage of transmembrane proteins. The lipid environment forms membrane microdomains that serve as spatio-temporal platforms for proteins to function properly. Despite substantial advances in the regulation of γ-secretase, the effect of the local membrane lipid microenvironment on the regulation of γ-secretase is poorly understood. Here, we characterized and quantified the partitioning of γ-secretase and its substrates, the amyloid precursor protein (APP) and Notch, into lipid bilayers using solid-supported model membranes. Notch substrate is preferentially localized in the liquid-disordered (Ld) lipid domains, whereas APP and γ-secretase partition as single or higher complex in both phases but highly favor the ordered phase, especially after recruiting lipids from the ordered phase, indicating that the activity and specificity of γ-secretase against these two substrates are modulated by membrane lateral organization. Moreover, time-elapse measurements reveal that γ-secretase can recruit specific membrane components from the cholesterol-rich Lo phase and thus creates a favorable lipid environment for substrate recognition and therefore activity. This work offers insight into how γ-secretase and lipid modulate each other and control its activity and specificity.

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SN - 0743-7463

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EP - 6579

JO - Langmuir

JF - Langmuir

IS - 23

ER -

γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion

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