GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity
Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the lumin...
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| Format: | Article |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.702508/full |
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| author | Kristian Kølby Kristensen Kristian Kølby Kristensen Katrine Zinck Leth-Espensen Katrine Zinck Leth-Espensen Anni Kumari Anni Kumari Anne Louise Grønnemose Anne Louise Grønnemose Anne-Marie Lund-Winther Anne-Marie Lund-Winther Stephen G. Young Stephen G. Young Michael Ploug Michael Ploug |
| author_facet | Kristian Kølby Kristensen Kristian Kølby Kristensen Katrine Zinck Leth-Espensen Katrine Zinck Leth-Espensen Anni Kumari Anni Kumari Anne Louise Grønnemose Anne Louise Grønnemose Anne-Marie Lund-Winther Anne-Marie Lund-Winther Stephen G. Young Stephen G. Young Michael Ploug Michael Ploug |
| author_sort | Kristian Kølby Kristensen |
| collection | DOAJ |
| description | Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL’s dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL’s hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL’s hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3–ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL–GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond–rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis. |
| first_indexed | 2024-12-14T15:48:48Z |
| format | Article |
| id | doaj.art-90d2661935c3460c90812ea384db77fa |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-14T15:48:48Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-90d2661935c3460c90812ea384db77fa2022-12-21T22:55:26ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-07-01910.3389/fcell.2021.702508702508GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL ActivityKristian Kølby Kristensen0Kristian Kølby Kristensen1Katrine Zinck Leth-Espensen2Katrine Zinck Leth-Espensen3Anni Kumari4Anni Kumari5Anne Louise Grønnemose6Anne Louise Grønnemose7Anne-Marie Lund-Winther8Anne-Marie Lund-Winther9Stephen G. Young10Stephen G. Young11Michael Ploug12Michael Ploug13Finsen Laboratory, Rigshospitalet, Copenhagen, DenmarkBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkFinsen Laboratory, Rigshospitalet, Copenhagen, DenmarkBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkFinsen Laboratory, Rigshospitalet, Copenhagen, DenmarkBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkFinsen Laboratory, Rigshospitalet, Copenhagen, DenmarkBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkFinsen Laboratory, Rigshospitalet, Copenhagen, DenmarkBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkDepartments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesFinsen Laboratory, Rigshospitalet, Copenhagen, DenmarkBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkIntravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL’s dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL’s hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL’s hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3–ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL–GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond–rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis.https://www.frontiersin.org/articles/10.3389/fcell.2021.702508/fullGPIHBP1lipoprotein lipaseintravascular lipolysisintrinsic disorderANGPTL4LU domain |
| spellingShingle | Kristian Kølby Kristensen Kristian Kølby Kristensen Katrine Zinck Leth-Espensen Katrine Zinck Leth-Espensen Anni Kumari Anni Kumari Anne Louise Grønnemose Anne Louise Grønnemose Anne-Marie Lund-Winther Anne-Marie Lund-Winther Stephen G. Young Stephen G. Young Michael Ploug Michael Ploug GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity Frontiers in Cell and Developmental Biology GPIHBP1 lipoprotein lipase intravascular lipolysis intrinsic disorder ANGPTL4 LU domain |
| title | GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity |
| title_full | GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity |
| title_fullStr | GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity |
| title_full_unstemmed | GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity |
| title_short | GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity |
| title_sort | gpihbp1 and angptl4 utilize protein disorder to orchestrate order in plasma triglyceride metabolism and regulate compartmentalization of lpl activity |
| topic | GPIHBP1 lipoprotein lipase intravascular lipolysis intrinsic disorder ANGPTL4 LU domain |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.702508/full |
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