scholarly journals The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Simon Mysling ◽  
Kristian Kølby Kristensen ◽  
Mikael Larsson ◽  
Oleg Kovrov ◽  
André Bensadouen ◽  
...  
Keyword(s):  
Lipoprotein Lipase ◽  
Molecular Basis ◽  
Plasma Triglyceride ◽  
Lower Plasma ◽  
Genetic Studies ◽  
Molecular Defects ◽  
Intrinsically Disordered ◽  
Acidic Domain ◽  
Physiological Relevance ◽  
Α Helix

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.

scholarly journals Structure of the lipoprotein lipase–GPIHBP1 complex that mediates plasma triglyceride hydrolysis

2018 ◽  
Vol 116 (5) ◽  
pp. 1723-1732 ◽  
Author(s):  
Gabriel Birrane ◽  
Anne P. Beigneux ◽  
Brian Dwyer ◽  
Bettina Strack-Logue ◽  
Kristian Kølby Kristensen ◽  
...  
Keyword(s):  
Lipoprotein Lipase ◽  
Hydrophobic Interactions ◽  
Cell Protein ◽  
Loss Of Function ◽  
Intrinsically Disordered ◽  
Acidic Domain ◽  
Triglyceride Hydrolysis ◽  
Severe Hypertriglyceridemia ◽  
Domain Loss ◽  
Lu Domain

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.

scholarly journals The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Simon Mysling ◽  
Kristian Kølby Kristensen ◽  
Mikael Larsson ◽  
Anne P Beigneux ◽  
Henrik Gårdsvoll ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Lipoprotein Lipase ◽  
Catalytic Domain ◽  
Exchange Mass Spectrometry ◽  
Intrinsically Disordered ◽  
Acidic Domain ◽  
Terminal Domain ◽  
Capillary Endothelial Cells ◽  
Hydrogen Deuterium ◽  
Deuterium Exchange Mass Spectrometry

GPIHBP1 is a glycolipid-anchored membrane protein of capillary endothelial cells that binds lipoprotein lipase (LPL) within the interstitial space and shuttles it to the capillary lumen. The LPL•GPIHBP1 complex is responsible for margination of triglyceride-rich lipoproteins along capillaries and their lipolytic processing. The current work conceptualizes a model for the GPIHBP1•LPL interaction based on biophysical measurements with hydrogen-deuterium exchange/mass spectrometry, surface plasmon resonance, and zero-length cross-linking. According to this model, GPIHBP1 comprises two functionally distinct domains: (1) an intrinsically disordered acidic N-terminal domain; and (2) a folded C-terminal domain that tethers GPIHBP1 to the cell membrane by glycosylphosphatidylinositol. We demonstrate that these domains serve different roles in regulating the kinetics of LPL binding. Importantly, the acidic domain stabilizes LPL catalytic activity by mitigating the global unfolding of LPL's catalytic domain. This study provides a conceptual framework for understanding intravascular lipolysis and GPIHBP1 and LPL mutations causing familial chylomicronemia.

76 Lipoprotein lipase −93T/G transition is associated with lower plasma triglyceride levels and increased promoter activity in vitro

1997 ◽  
Vol 130 ◽  
pp. S20 ◽  
Author(s):  
Philippa Talmud ◽  
Stephen Hall ◽  
Grace Chu ◽  
John Yudkin ◽  
George Miller ◽  
...  
Keyword(s):  
Lipoprotein Lipase ◽  
Promoter Activity ◽  
Plasma Triglyceride ◽  
Lower Plasma

The Lipoprotein Lipase Hin dIII Polymorphism Modulates Plasma Triglyceride Levels in Visceral Obesity

1995 ◽  
Vol 15 (5) ◽  
pp. 714-720 ◽  
Author(s):  
Marie-Claude Vohl ◽  
Benoı̂t Lamarche ◽  
Sital Moorjani ◽  
Denis Prud’homme ◽  
André Nadeau ◽  
...  
Keyword(s):  
Lipoprotein Lipase ◽  
Visceral Obesity ◽  
Plasma Triglyceride

scholarly journals Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis

2017 ◽  
Vol 114 (32) ◽  
pp. E6507-E6515 ◽  
Author(s):  
Shobini Jayaraman ◽  
Donald L. Gantz ◽  
Christian Haupt ◽  
Olga Gursky
Keyword(s):  
Serum Amyloid A ◽  
Major Complication ◽  
Lipid Vesicles ◽  
Serum Amyloid ◽  
High Density Lipoproteins ◽  
Aa Amyloidosis ◽  
Intrinsically Disordered ◽  
Amyloid A ◽  
Α Helix ◽  
Structural Methods

Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5–4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5–4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.

Lipoprotein lipase activity in rat heart and adipose tissue during endotoxic shock

1980 ◽  
Vol 238 (3) ◽  
pp. H325-H330 ◽  
Author(s):  
G. J. Bagby ◽  
J. A. Spitzer
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipoprotein Lipase ◽  
Endotoxic Shock ◽  
Plasma Triglyceride ◽  
Lipoprotein Lipase Activity ◽  
Fat Pad ◽  
E Coli ◽  
Adipose Tissue Lipoprotein Lipase ◽  
Observation Period

The present studies were designed to delineate changes in heart and adipose tissue lipoprotein lipase (LPL) activity following the administration of E. coli endotoxin. Plasma triglyceride levels were elevated in animals given endotoxin compared to saline-injected controls. Heart LPL activity decreased from 126.4 mumol fatty acid released per gram wet wt per hour in control rats to less than 22.5 mumol . g-1 . h-1 by 7 h following the injection of endotoxin. Although endotoxin was administered in doses producing 0-100% mortalities in a 24-h period, myocardial LPL activity was depressed to the same extent (75-80%) regardless of dose. The response of adipose tissue was less pronounced. Epididymal fat pad LPL activity fell significantly over the 24-h observation period in control and endotoxin-treated rats with the latter group somewhat more depressed 7 h after treatment. The findings are consistent with the suggestion that hypertriglyceridemia often observed during endotoxic shock may be related to depressed LPL activity; the degree of depression is probably tissue dependent.

scholarly journals Evolutionary conservation of the intrinsic disorder-based Radical-Induced Cell Death1 hub interactome

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lise Friis Christensen ◽  
Lasse Staby ◽  
Katrine Bugge ◽  
Charlotte O’Shea ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stress Responses ◽  
Plant Stress ◽  
Three Dimensional ◽  
Intrinsic Disorder ◽  
Dimensional Structure ◽  
Linear Motif ◽  
Intrinsically Disordered ◽  
Helix Formation ◽  
Α Helix

AbstractRadical-Induced Cell Death1 (RCD1) functions as a cellular hub interacting with intrinsically disordered transcription factor regions, which lack a well-defined three-dimensional structure, to regulate plant stress. Here, we address the molecular evolution of the RCD1-interactome. Using bioinformatics, its history was traced back more than 480 million years to the emergence of land plants with the RCD1-binding short linear motif (SLiM) identified from mosses to flowering plants. SLiM variants were biophysically verified to be functional and to depend on the same RCD1 residues as the DREB2A transcription factor. Based on this, numerous additional members may be assigned to the RCD1-interactome. Conservation was further strengthened by similar intrinsic disorder profiles of the transcription factor homologs. The unique structural plasticity of the RCD1-interactome, with RCD1-binding induced α-helix formation in DREB2A, but not detectable in ANAC046 or ANAC013, is apparently conserved. Thermodynamic analysis also indicated conservation with interchangeability between Arabidopsis and soybean RCD1 and DREB2A, although with fine-tuned co-evolved binding interfaces. Interruption of conservation was observed, as moss DREB2 lacked the SLiM, likely reflecting differences in plant stress responses. This whole-interactome study uncovers principles of the evolution of SLiM:hub-interactions, such as conservation of α-helix propensities, which may be paradigmatic for disorder-based interactomes in eukaryotes.

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