Cleavage and functional loss of human apolipoprotein E by digestion of matrix metalloproteinase-14

Hyoung Park Jun, Sung Min Park, Sun Hyun Park, Kyung Hyun Cho, Seung Taek Lee

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10 Citations (Scopus)


By means of a degradomic approach applying proteomic techniques, we previously suggested that apolipoprotein E (apoE) is a substrate of matrix metalloproteinase-14 (MMP-14). Here we confirm that apoE is, in fact, a substrate of MMP-14 and also of MMP-7 and MMP-2 to a lesser extent. The 34 kDa apoE protein was initially processed by MMP-14 into fragments with molecular masses of 28, 23, 21, and 11 kDa. MMP-14 cleavage sites within the apoE protein were determined by C-terminal labeling of MMP-14-digested apoE fragments with isotope (18O/16O = 1:1) and identification of the doublet fragments or peptides showing 2 Da difference by MS, along with N-terminal sequencing of the fragments. It was determined that the primary MMP-14 cleavage sites were A176-I177, P183-L184, P202-L203, and Q249-T250. The MMP-14-mediated cleavage of apoE was consistent regardless of whether apoE existed in its lipid-bound or lipid-free form. Upon digestion with MMP-14, apoE loses its ability to suppress the platelet-derived growth factor-induced migration of rat vascular smooth muscle cells. Considering the important role of apoE for lipid metabolism and atherosclerosis protection, our findings suggest that MMP-14 plays an essential role for the development of hyperlipidemia and atherosclerosis as a result of degradation of apoE.

Original languageEnglish
Pages (from-to)2926-2935
Number of pages10
Issue number14
Publication statusPublished - 2008 Jul

Bibliographical note

Funding Information:
Sandia is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin Company, of the United States Department of Energy's National Nuclear Security Administration under Contract DE-AC04-94AL85000. This work was partially funded by Sandia's LDRD program. The authors also acknowledge Eric Coker (Sandia) for providing the N2 and Ar BET absorption data.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology


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