PCSK6,FURIN mediate dissociation of 2 x LPL from GPIHBP1:HSPG:LPL dimer

Stable Identifier
R-HSA-6784628
Type
Reaction [transition]
Species
Homo sapiens
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LPL enzyme is catalytically active as a dimer composed of two glycosylated subunits of LPL connected in a head-to-tail arrangement by non-covalent interactions. Dimeric LPL is cleaved by several proprotein convertases. FURIN and proprotein convertase subtilisin/kexin type 6 (PCSK6 aka PACE4) can cleave LPL dimer, inactivating it, resulting in subsequent increase in plasma TG concentrations (Siezen et al. 1994, Bassi et al. 2000, Jin et al. 2005). Endogenous modulators of LPL are the angiopoietin-like proteins ANGPTL3 and ANGPTL4, which can bind transiently to LPL dimer, resulting in conversion of the enzyme from a catalytically active dimer to inactive, but still folded, monomers (Liu et al. 2010, Sukonina et al. 2006). ANGPTL4 regulates plasma triglyceride concentration via the inhibition of LPL (Dijk & Kersten 2014). GWAS studies (Dewey et al. 2016, MIG and CARDIoGRAM Consortium 2016) show a strong correlation between inactivating ANGPTL4 mutants and lower levels of triglycerides and lower risk of coronary artery disease than non-carriers. Therapeutic modulation of ANGPTL4 could be a new strategy against dyslipidemia (Kersten 2016).

Literature References
PubMed ID Title Journal Year
8020465 Homology modelling of the catalytic domain of human furin. A model for the eukaryotic subtilisin-like proprotein convertases

Siezen, RJ, Creemers, JW, Van de Ven, WJ

Eur. J. Biochem. 1994
26933753 Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease

Dewey, FE, Gusarova, V, O'Dushlaine, C, Gottesman, O, Trejos, J, Hunt, C, Van Hout, CV, Habegger, L, Buckler, D, Lai, KM, Leader, JB, Murray, MF, Ritchie, MD, Kirchner, HL, Ledbetter, DH, Penn, J, Lopez, A, Borecki, IB, Overton, JD, Reid, JG, Carey, DJ, Murphy, AJ, Yancopoulos, GD, Baras, A, Gromada, J, Shuldiner, AR

N. Engl. J. Med. 2016
17088546 Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue

Sukonina, V, Lookene, A, Olivecrona, T, Olivecrona, G

Proc. Natl. Acad. Sci. U.S.A. 2006
20581395 Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases

Liu, J, Afroza, H, Rader, DJ, Jin, W

J. Biol. Chem. 2010
26934667 The Genetics of Dyslipidemia--When Less Is More

Kersten, S

N. Engl. J. Med. 2016
24397894 Regulation of lipoprotein lipase by Angptl4

Dijk, W, Kersten, S

Trends Endocrinol. Metab. 2014
16109723 Proprotein convertases [corrected] are responsible for proteolysis and inactivation of endothelial lipase

Jin, W, Fuki, IV, Seidah, NG, Benjannet, S, Glick, JM, Rader, DJ

J. Biol. Chem. 2005
10900462 The proprotein convertases furin and PACE4 play a significant role in tumor progression

Bassi, DE, Mahloogi, H, Klein-Szanto, AJ

Mol. Carcinog. 2000
26934567 Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, -

N. Engl. J. Med. 2016
Participants
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Catalyst Activity
Title
endopeptidase activity of FURIN,PCSK6 [extracellular region]
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This event is regulated
Orthologous Events
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