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J. Biol. Chem., Vol. 279, Issue 3, 2038-2045, January 16, 2004

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Oligomerization and Regulated Proteolytic Processing of Angiopoietin-like Protein 4^*

Hongfei Ge, Guoqing Yang, Lu Huang¶, Daniel L. Motola, Tiffany Pourbahrami, and Cai Li||**

From the Touchstone Center for Diabetes Research and the Departments of Physiology and ^||Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854

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)- 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.

Received for publication, July 14, 2003 , and in revised form, October 10, 2003.

Note Added in Proof—While this manuscript was under review, Ono et al. (Ono, M., Shimizugawa, T., Shimamura, M., Yoshida, K., Noji-Sakikawa, C., Ando, Y., Koishi, R., and Furukawa, H. (2003) J. Biol. Chem. 278, 41804–41809) also reported the proteolytic cleavage of angiopoietin-like 3, a protein sharing homology with Angptl4.

^* This work was supported in part by National Institutes of Health Grant DK60137. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY393999.

^¶ Present address: Shanghai Haojia Technology Development Co. Ltd., Shanghai 200235, China.

Recipient of a Career Development Award from the American Diabetes Association.

^** To whom reprint requests should be addressed: 5323 Harry Hines Blvd., Dallas, TX 75390-8854. Tel.: 214-648-3340; Fax: 214-648-9191; E-mail: cai.li{at}utsouthwestern.edu.

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