4.5 Article

Molecular basis for the protective effects of low-density lipoprotein receptor-related protein 1 (LRP1)-derived peptides against LDL aggregation

期刊

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
卷 1861, 期 7, 页码 1302-1316

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2019.05.003

关键词

Lipoprotein aggregation; LRP1-derived peptides; ApoB-100; SMase, PLA(2), atherosclerosis

资金

  1. Ministry of Science and Innovation of Spain, in the framework of the State Plan of Scientific and Technical Innovation Investigation [RTC-2016-5078-1]
  2. Ministry of Economy, Industry and Competitiveness (MINECO)
  3. European Union
  4. European Regional Development Fund (ERDF)
  5. Fundacio la Marato de TV3 Project [201521-10]
  6. Instituto de Salud Carlos III (ISCIII) [FIS PI13/00364, PI16/00471, FIS PI18/01584, CB16/1100403, CB07/08/0016, PT17/0019]
  7. ERDF
  8. Ministerio de Economia y Competitividad [IJCI-2016-29393]
  9. Spanish Ministry of Economy and Competitiveness [SEV-2012-0208, 2017SGR595, 2017SGR946]
  10. [SAF2017-89613R]

向作者/读者索取更多资源

Aggregated LDL is the first ligand reported to interact with the cluster II CR9 domain of low-density lipoprotein receptor-related protein 1 (LRP1). In particular, the C-terminal half of domain CR9, comprising the region Gly(1127)-Cys(1140) exclusively recognizes aggregated LDL and it is crucial for aggregated LDL binding. Our aim was to study the effect of the sequence Gly(1127)-Cys(1140) (named peptide LP3 and its retro-enantio version, named peptide DP3) on the structural characteristics of sphingomyelinase- (SMase) and phospholipase 2 (PLA(2))-modified LDL particles. Turbidimetry, gel filtration chromatography (GFC) and transmission electronic microscopy (TEM) analysis showed that LP3 and DP3 peptides strongly inhibited SMase- and PLA(2)-induced LDL aggregation. Nondenaturing polyacrylamide gradient gel electrophoresis (GGE), agarose gel electrophoresis and high-performance thin-layer chromatography (HPTLC) indicated that LP3 and DP3 prevented SMase-induced alterations in LDL particle size, electric charge and phospholipid content, respectively, but not those induced by PLA(2). Western blot analysis showed that LP3 and DP3 counteracted changes in ApoB-100 conformation induced by the two enzymes. LDL proteomics (LDL trypsin digestion followed by mass spectroscopy) and computational modeling methods evidenced that peptides preserve ApoB-100 conformation due to their electrostatic interactions with a basic region of ApoB-100. These results demonstrate that LRP1-derived peptides are protective against LDL aggregation, even in conditions of extreme lipolysis, through their capacity to bind to ApoB-100 regions critical for ApoB-100 conformational preservation. These results suggests that these LRP1(CR9) derived peptides could be promising tools to prevent LDL aggregation induced by the main proteolytic enzymes acting in the arterial intima.

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