Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis
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Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis. / Birrane, Gabriel; Beigneux, Anne P; Dwyer, Brian; Strack-Logue, Bettina; Kristensen, Kristian Kølby; Francone, Omar L; Fong, Loren G; Mertens, Haydyn D T; Pan, Clark Q; Ploug, Michael; Young, Stephen G; Meiyappan, Muthuraman.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 5, 2019, p. 1723-1732.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
N1 - Copyright © 2019 the Author(s). Published by PNAS.
PY - 2019
Y1 - 2019
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
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
SN - 0027-8424
IS - 5
ER -
ID: 216914567