Structural insights into recognition of beta2-glycoprotein I by the lipoprotein receptors.
The interactions of beta2 glycoprotein I (B2GPI) with the receptors of the low-density lipoprotein receptor (LDLR) family are implicated in the clearance of negatively charged phospholipids and apoptotic cells and, in the presence of autoimmune anti-B2GPI antibodies, in cell activation, which might play a role in the pathology of antiphospholipid syndrome (APS). The ligand-binding domains of the lipoprotein receptors consist of multiple homologous LA modules connected by flexible linkers. In this study, we investigated at the atomic level the features of the LA modules required for binding to B2GPI. To compare the binding interface in B2GPI/LA complex to that observed in the high-resolution co-crystal structure of the receptor associated protein (RAP) with a pair of LA modules 3 and 4 from the LDLR, we used LA4 in our studies. Using solution NMR spectroscopy, we found that LA4 interacts with B2GPI and the binding site for B2GPI on the (15)N-labeled LA4 is formed by the calcium coordinating residues of the LA module. We built a model for the complex between domain V of B2GPI (B2GPI-DV) and LA4 without introducing any experimentally derived constraints into the docking procedure. Our model, which is in the agreement with the NMR data, suggests that the binding interface of B2GPI for the lipoprotein receptors is centered at three lysine residues of B2GPI-DV, Lys 308, Lys 282, and Lys317.
Beglov
Dmitri
D
Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA.
Lee
Chang-Jin
CJ
De Biasio
Alfredo
A
Kozakov
Dima
D
Brenke
Ryan
R
Vajda
Sandor
S
Beglova
Natalia
N
D001665:Binding Sites; D006801:Humans; D066298:In Vitro Techniques; D008239:Lysine / Q000737:chemistry; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D013816:Thermodynamics; D053482:beta 2-Glycoprotein I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D053482:beta 2-Glycoprotein I; D008239:Lysine
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