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The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding
Abstract
Lipoprotein lipase (LPL) undergoes spontaneous inactivation via global unfolding and this unfolding is prevented by GPIHBP1 ( Mysling et al., 2016 ). We now show: (1) that ANGPTL4 inactivates LPL by catalyzing the unfolding of its hydrolase domain; (2) that binding to GPIHBP1 renders LPL largely refractory to this inhibition; and (3) that both the LU domain and the intrinsically disordered acidic domain of GPIHBP1 are required for this protective effect. Genetic studies have found that a common polymorphic variant in ANGPTL4 results in lower plasma triglyceride levels. We now report: (1) that this ANGPTL4 variant is less efficient in catalyzing the unfolding of LPL; and (2) that its Glu-to-Lys substitution destabilizes its N-terminal α-helix. Our work elucidates the molecular basis for regulation of LPL activity by ANGPTL4, highlights the physiological relevance of the inherent instability of LPL, and sheds light on the molecular defects in a clinically relevant variant of ANGPTL4.
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Multiple laboratories have confirmed the ability of ANGPTL4 to inhibit LPL.
“In the years since, multiple laboratories have confirmed the ability of ANGPTL4 to inhibit LPL (49–55).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [52]
ANGPTL3 could inhibit LPL by unfolding or sterically changing the active domain of LPL, though its potency was far less than that of ANGPTL4.
“In contrast, Mysling et al. (52) found that, like ANGPTL4, ANGPTL3 could inhibit LPL by unfolding or sterically changing the active domain of LPL, though its potency was far less than that of ANGPTL4.”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [52]
Vascular LPL, bound to its receptor GPIHBP1, is protected from ANGPTL4 inhibition.
“In fact, several studies have found that vascular LPL, bound to its receptor GPIHBP1, is protected from ANGPTL4 inhibition (51, 52, 60).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [52]
ANGPTL4 can act on monomeric LPL and increases the inherent instability of LPL resulting in unfolding of LPL's catalytic domain.
“Indeed, a recent series of studies from the laboratory of Michael Ploug have shown that ANGPTL4 can act on monomeric LPL, and that ANGPTL4 increases the inherent instability of LPL resulting in the unfolding of LPL’s catalytic domain (52, 97, 98).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [52]
Several studies have indicated that ANGPTL4 catalytically inactivates LPL.
“Several studies have indicated that ANGPTL4 catalytically inactivates LPL (49, 51, 52, 97, 98).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [52]
LPL bound to GPIHBP1 is largely protected from ANGPTL4.
“LPL bound to GPIHBP1 is largely protected from ANGPTL4 (51, 52, 60, 98).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [52]
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Citations
Cites
Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease
Dewey, F. E., Gusarova, V., O’Dushlaine, C., Gottesman, O., Trejos, J., Hunt, C., Van Hout, C. V., Habegger, L., Buckler, D., Lai, K.-M. V., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1510926 · Cited by 497
Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1507652 · Cited by 493
Köster, A., Chao, Y. B., Mosior, M., Ford, A., Gonzalez-DeWhitt, P. A., Hale, J. E., Li, D., Qiu, Y., Fraser, C. C., Yang, D. D., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0476 · Cited by 427 · cited 1×
“DOI: 10.7554/eLife.20958.001”
InfluentialMutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia.
Olivecrona, G., Ehrenborg, E., Semb, H., Makoveichuk, E., Lindberg, A., Hayden, M. R., Gin, P., Davies, B. S. J., Weinstein, M. M., Fong, L. G., et al. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m002717 · Cited by 118 · cited 2×
“, 2007) or by loss-of-function missense mutations in humans leads to sustained elevations in plasma triglyceride levels—a condition known as familial chylomicronemia (Ariza et al., 2016; Beigneux et al., 2015, 2009b; Olivecrona et al., 2010; Plengpanich et al., 2014).”
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Metadata
- Authors
- Mysling, S., Kristensen, K. K., Larsson, M., Kovrov, O., Bensadouen, A., Jørgensen, T. J., Olivecrona, G., Young, S. G., & Ploug, M.
- Affiliations
- Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
- Department of Medicine, University of California, Los Angeles, Los Angeles, United States
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
- Division of Nutritional Science, Cornell University, Ithaca, United States
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
- ORCID
- Ploug, Michael
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-12-08
- Volume
- 5
- ISSN
- 2050-084X
- PMC
- PMC5148603
- Cited by
- 77
- References
- 4
- Language
- en
- Licence
- Funders
- Leducq Transatlantic Network (12CVD04)
- National Institutes of Health (HL090553, HL087228)
- Rigshospitalet (123)
- Swedish Research Council for Medicine and Health (2015-02942)
- Swedish Heart and Lung Foundation (20130684)
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