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Region Hovedstaden - en del af Københavns Universitetshospital
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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

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  1. ANGPTL4 inactivates lipoprotein lipase by catalyzing the irreversible unfolding of LPL's hydrolase domain

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Intermittent chylomicronemia caused by intermittent GPIHBP1 autoantibodies

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Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskrifteLife
Vol/bind5
Sider (fra-til)e20958
ISSN2050-084X
DOI
StatusUdgivet - 8 dec. 2016

ID: 49464183