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

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

Stable Identifier

R-HSA-6784628

Type

Reaction [transition]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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

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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
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
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
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