LDL receptor/lipoprotein recognition: endosomal weakening of ApoB and ApoE binding to the convex face of the LR5 repeat

Authors

  • Juan Martínez-Oliván,

    1. Biocomputation and Complex Systems Physics Institute (BIFI). BIFI-Instituto de Química Física Rocasolano (Consejo Superior de Investigaciones Científicas) Joint Unit, Universidad de Zaragoza, Spain
    2. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Spain
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  • Xabier Arias-Moreno,

    1. Biocomputation and Complex Systems Physics Institute (BIFI). BIFI-Instituto de Química Física Rocasolano (Consejo Superior de Investigaciones Científicas) Joint Unit, Universidad de Zaragoza, Spain
    2. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Spain
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  • Adrián Velazquez-Campoy,

    1. Biocomputation and Complex Systems Physics Institute (BIFI). BIFI-Instituto de Química Física Rocasolano (Consejo Superior de Investigaciones Científicas) Joint Unit, Universidad de Zaragoza, Spain
    2. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Spain
    3. Fundación Agencia Aragonesa para la Investigación y Desarrollo, Diputación General de Aragón, Spain
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  • Oscar Millet,

    1. Structural Biology Unit, CIC bioGUNE, Derio, Spain
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  • Javier Sancho

    Corresponding author
    1. Biocomputation and Complex Systems Physics Institute (BIFI). BIFI-Instituto de Química Física Rocasolano (Consejo Superior de Investigaciones Científicas) Joint Unit, Universidad de Zaragoza, Spain
    2. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Spain
    • Correspondence

      J. Sancho, Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain

      Fax: +34 976762123

      Tel: +34 976761286

      E-mail: jsancho@unizar.es

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Abstract

The molecular mechanism of lipoprotein binding by the low-density lipoprotein (LDL) receptor (LDLR) is poorly understood, one reason being that structures of lipoprotein–receptor complexes are not available. LDLR uses calcium-binding repeats (LRs) to interact with apolipoprotein B and apolipoprotein E (ApoB and ApoE). We have used NMR and SPR to characterize the complexes formed by LR5 and three peptides encompassing the putative binding regions of ApoB (site A and site B) and ApoE. The three peptides bind at the hydrophilic convex face of LR5, forming complexes that are weakened at low [Ca2+] and low pH. Thus, endosomal conditions favour dissociation of LDLR/lipoprotein complexes regardless of whether active displacement of bound lipoproteins by the β-propeller in LDLR takes place. The multiple ApoE copies in β very low density lipoproteins (β-VLDLs), and the presence of two competent binding sites (A and B) in LDLs, suggest that LDLR chelates lipoproteins and enhances complex affinity by using more than one LR.

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