Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis

Gabriel Birrane; Anne P Beigneux; Brian Dwyer; Bettina Strack-Logue; Kristian Kølby Kristensen; Omar L Francone; Loren G Fong; Haydyn D T Mertens; Clark Q Pan; Michael Ploug; Stephen G Young; Muthuraman Meiyappan

doi:10.1073/pnas.1817984116

Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis

Gabriel Birrane, Anne P Beigneux, Brian Dwyer, Bettina Strack-Logue, Kristian Kølby Kristensen, Omar L Francone, Loren G Fong, Haydyn D T Mertens, Clark Q Pan, Michael Ploug, Stephen G Young, Muthuraman Meiyappan

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Abstract

Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	5
Pages (from-to)	1723-1732
Number of pages	10
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1817984116
Publication status	Published - 29 Jan 2019

Keywords

Animals
CHO Cells
Capillaries/metabolism
Cell Line
Cricetulus
Crystallography, X-Ray/methods
Endothelial Cells/metabolism
Humans
Hydrolysis
Hypertriglyceridemia/metabolism
Lipoprotein Lipase/metabolism
Plasma/metabolism
Receptors, Lipoprotein/metabolism
Triglycerides/blood

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Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysisFinal published version, 2.37 MBLicence: CC BY-NC-ND

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Birrane, G., Beigneux, A. P., Dwyer, B., Strack-Logue, B., Kristensen, K. K., Francone, O. L., Fong, L. G., Mertens, H. D. T., Pan, C. Q., Ploug, M., Young, S. G., & Meiyappan, M. (2019). Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis. Proceedings of the National Academy of Sciences of the United States of America, 116(5), 1723-1732. https://doi.org/10.1073/pnas.1817984116

Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis. / Birrane, Gabriel; Beigneux, Anne P; Dwyer, Brian et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 5, 29.01.2019, p. 1723-1732.

Research output: Contribution to journal › Journal article › Research › peer-review

Birrane, G, Beigneux, AP, Dwyer, B, Strack-Logue, B, Kristensen, KK, Francone, OL, Fong, LG, Mertens, HDT, Pan, CQ, Ploug, M, Young, SG & Meiyappan, M 2019, 'Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 5, pp. 1723-1732. https://doi.org/10.1073/pnas.1817984116

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title = "Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis",

abstract = "Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia.",

keywords = "Animals, CHO Cells, Capillaries/metabolism, Cell Line, Cricetulus, Crystallography, X-Ray/methods, Endothelial Cells/metabolism, Humans, Hydrolysis, Hypertriglyceridemia/metabolism, Lipoprotein Lipase/metabolism, Plasma/metabolism, Receptors, Lipoprotein/metabolism, Triglycerides/blood",

author = "Gabriel Birrane and Beigneux, {Anne P} and Brian Dwyer and Bettina Strack-Logue and Kristensen, {Kristian K{\o}lby} and Francone, {Omar L} and Fong, {Loren G} and Mertens, {Haydyn D T} and Pan, {Clark Q} and Michael Ploug and Young, {Stephen G} and Muthuraman Meiyappan",

note = "Copyright {\textcopyright} 2019 the Author(s). Published by PNAS.",

year = "2019",

month = jan,

day = "29",

doi = "10.1073/pnas.1817984116",

language = "English",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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T1 - Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis

AU - Birrane, Gabriel

AU - Beigneux, Anne P

AU - Dwyer, Brian

AU - Strack-Logue, Bettina

AU - Kristensen, Kristian Kølby

AU - Francone, Omar L

AU - Fong, Loren G

AU - Mertens, Haydyn D T

AU - Pan, Clark Q

AU - Ploug, Michael

AU - Young, Stephen G

AU - Meiyappan, Muthuraman

PY - 2019/1/29

Y1 - 2019/1/29

N2 - Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia.

AB - Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia.

KW - Animals

KW - CHO Cells

KW - Capillaries/metabolism

KW - Cell Line

KW - Cricetulus

KW - Crystallography, X-Ray/methods

KW - Endothelial Cells/metabolism

KW - Humans

KW - Hydrolysis

KW - Hypertriglyceridemia/metabolism

KW - Lipoprotein Lipase/metabolism

KW - Plasma/metabolism

KW - Receptors, Lipoprotein/metabolism

KW - Triglycerides/blood

U2 - 10.1073/pnas.1817984116

DO - 10.1073/pnas.1817984116

M3 - Journal article

C2 - 30559189

SN - 0027-8424

VL - 116

SP - 1723

EP - 1732

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 5

ER -

Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis

Abstract

Keywords

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