Oligomerization and regulated proteolytic processing of angiopoietin-like protein 4.
Angiopoietin-like protein 4 (Angptl4) is a recently identified circulating protein expressed primarily in adipose tissue and liver. Also known as peroxisome proliferator-activated receptor (PPAR)-gamma angiopoietin-related, fasting induced adipose factor, and hepatic fibrinogen/angiopoietin-related protein, recombinant Angptl4 causes increase of plasma very low density lipoprotein levels by inhibition of lipoprotein lipase activity. Similar to angiopoietins and other angiopoietin-like proteins, Angptl4 contains an amino-terminal coiled-coil domain and a carboxyl-terminal fibrinogen-like domain. We report here that Angptl4 is evolutionarily conserved among several mammalian species and that full-length Angptl4 protein is an oligomer containing intermolecular disulfide bonds. Oligomerized Angptl4 undergoes proteolytic processing to release its carboxyl fibrinogen-like domain, which circulates as a monomer. Angptl4's N-terminal coiled-coil domain mediates its oligomerization, which by itself is sufficient to form higher order oligomeric structure. Adenovirus-mediated overexpression of Angptl4 in 293 cells shows that conversion of full-length, oligomerized Angptl4 is mediated by a cell-associated protease activity induced by serum. These findings demonstrate a novel property of angiopoietin-like proteins and suggest that oligomerization and proteolytic processing of Angptl4 may regulate its biological activities in vivo.
Touchstone Center for Diabetes Research and Departments of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8854, USA.
Hongfei
H
Ge
Guoqing
G
Yang
Lu
L
Huang
Daniel L
DL
Motola
Tiffany
T
Pourbahrami
Cai
C
Li
D000595:Amino Acid Sequence; D000091302:Angiopoietin-Like Protein 2; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry* / Q000502:physiology; D017124:Conserved Sequence; D016895:Culture Media, Serum-Free; D004220:Disulfides / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats
C485792:ANGPTL2 protein, human; C474772:ANGPTL4 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D001798:Blood Proteins; D016895:Culture Media, Serum-Free; D004220:Disulfides; D036341:Intercellular Signaling Peptides and Proteins