LDL receptor/lipoprotein recognition: endosomal weakening of ApoB and ApoE binding to the convex face of the LR5 repeat.
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 [Ca(2+) ] 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.
Biocomputation and Complex Systems Physics Institute (BIFI). BIFI-Instituto de Química Física Rocasolano (Consejo Superior de Investigaciones Científicas) Joint Unit, Universidad de Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Spain.
Juan
J
Martínez-Oliván
Xabier
X
Arias-Moreno
Adrián
A
Velazquez-Campoy
Oscar
O
Millet
Javier
J
Sancho
D000595:Amino Acid Sequence; D000818:Animals; D053318:Apolipoprotein E3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001055:Apolipoproteins B / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D017124:Conserved Sequence; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011973:Receptors, LDL / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance; D014714:Vertebrates / Q000235:genetics / Q000378:metabolism
D053318:Apolipoprotein E3; D001055:Apolipoproteins B; D046912:Multiprotein Complexes; D011973:Receptors, LDL; D011994:Recombinant Proteins; D002118:Calcium
ApoB; ApoE; NMR; SPR; low-density lipoprotein (LDL) receptor