Genetic Variation in ANGPTL4 Provides Insights into Protein Processing and Function

被引:103
作者
Yin, Wu [1 ]
Romeo, Stefano [1 ]
Chang, Shurong [1 ]
Grishin, Nick V. [2 ,3 ]
Hobbs, Helen H. [1 ,3 ]
Cohen, Jonathan C. [1 ,4 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dept Mol Genet, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA
[4] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA
基金
美国国家卫生研究院;
关键词
ANGIOPOIETIN-LIKE PROTEIN-4; LIPOPROTEIN-LIPASE; TARGET GENE; INHIBITION; OLIGOMERIZATION; MICE; LPL;
D O I
10.1074/jbc.M900553200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Angiopoietin-like protein 4 (ANGPTL4) is a secreted protein that modulates the disposition of circulating triglycerides (TG) by inhibiting lipoprotein lipase (LPL). Here we examine the steps involved in the synthesis and post-translational processing of ANGPTL4, and the effects of a naturally occurring sequence variant (E40K) that is associated with lower plasma TG levels in humans. Expression of the wild-type and mutant proteins in HEK-293A cells indicated that ANGPTL4 formed dimers and tetramers in cells prior to secretion and cleavage of the protein. After cleavage at a canonical proprotein convertase cleavage site ((RRKR164)-R-161), the oligomeric structure of the N-terminal domain was retained whereas the C-terminal fibrinogen-like domain dissociated into monomers. Inhibition of cleavage did not interfere with oligomerization of ANGPTL4 or with its ability to inhibit LPL, whereas mutations that prevented oligomerization severely compromised the capacity of the protein to inhibit LPL. ANGPTL4 containing the E40K substitution was synthesized and processed normally, but no monomers or oligomers of the N-terminal fragments accumulated in the medium; medium from these cells failed to inhibit LPL activity. Parallel experiments performed in mice recapitulated these results. Our findings indicate that oligomerization, but not cleavage, of ANGPTL4 is required for LPL inhibition, and that the E40K substitution destabilizes the protein after secretion, preventing the extracellular accumulation of oligomers and abolishing the ability of the protein to inhibit LPL activity.
引用
收藏
页码:13213 / 13222
页数:10
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