TY - JOUR TI - The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding AU - Mysling, Simon AU - Kristensen, Kristian Kølby AU - Larsson, Mikael AU - Kovrov, Oleg AU - Bensadouen, André AU - Jørgensen, Thomas JD AU - Olivecrona, Gunilla AU - Young, Stephen G AU - Ploug, Michael A2 - Glass, Christopher K VL - 5 PY - 2016 DA - 2016/12/08 SP - e20958 C1 - eLife 2016;5:e20958 DO - 10.7554/eLife.20958 UR - https://doi.org/10.7554/eLife.20958 AB - 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. KW - HDX-MS KW - GPIHBP1 KW - ANGTPL4 KW - ANGTPL3 KW - familial chylomicronemia KW - protein unfolding JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -