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.
Ge
Hongfei
H
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.
Yang
Guoqing
G
Huang
Lu
L
Motola
Daniel L
DL
Pourbahrami
Tiffany
T
Li
Cai
C
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