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Title: | Molecular basis for the protective effects of low-density lipoprotein receptor-related protein 1 (LRP1)-derived peptides against LDL aggregation |
Authors: | Benitez-Amaro, Aleyda; Pallara, Chiara; Nasarre, Laura; Rivas-Urbina,Andrea; Benítez, Sonia; Vea, Ángela; Bornachea, Olga; Gonzalo-Calvo, David de; Serra-Mir, Gabriel; Villegas, Sandra; Prades, Roger; Sánchez-Quesada, José Luís; Chiva, Cristina; Sabidó, Eduard; Tarragó, Teresa; Llorente-Cortés, Vicenta |
Keywords: | Lipoprotein aggregation LRP1-derived peptides ApoB-100 SMase, PLA2, atherosclerosis |
Issue Date: | 1-Jul-2019 |
Publisher: | Elsevier BV |
Citation: | Biochimica et Biophysica Acta - Biomembranes 1861(7): 1302-1316 (2019) |
Abstract: | 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 Gly1127-Cys1140 exclusively recognizes aggregated LDL and it is crucial for aggregated LDL binding. Our aim was to study the effect of the sequence Gly1127-Cys1140 (named peptide LP3 and its retro-enantio version, named peptide DP3) on the structural characteristics of sphingomyelinase- (SMase) and phospholipase 2 (PLA2)-modified LDL particles. Turbidimetry, gel filtration chromatography (GFC) and transmission electronic microscopy (TEM) analysis showed that LP3 and DP3 peptides strongly inhibited SMase- and PLA2-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 PLA2. 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. |
Publisher version (URL): | http://dx.doi.org/10.1016/j.bbamem.2019.05.003 |
URI: | http://hdl.handle.net/10261/201668 |
DOI: | 10.1016/j.bbamem.2019.05.003 |
Identifiers: | doi: 10.1016/j.bbamem.2019.05.003 issn: 1879-2642 |
Appears in Collections: | (IIBB) Artículos |
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