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Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor

Reimund, Mart, Dearborn, Altaira D., Graziano, Giorgio, Lei, Haotian, Ciancone, Anthony M., Kumar, Ashish, Holewinski, Ronald, Neufeld, Edward B., O’Reilly, Francis J., Remaley, Alan T., Marcotrigiano, Joseph·2025·Nature
DOI 10.1038/s41586-024-08223-0
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Abstract

Apolipoprotein B100 (apoB100) is a structural component of low-density lipoprotein (LDL) and a ligand for the LDL receptor (LDLR) 1 . Mutations in apoB100 or in LDLR cause familial hypercholesterolaemia, an autosomal dominant disease that is characterized by a marked increase in LDL cholesterol (LDL-C) and a higher risk of cardiovascular disease 2 . The structure of apoB100 on LDL and its interaction with LDLR are poorly understood. Here we present the cryo-electron microscopy structures of apoB100 on LDL bound to the LDLR and a nanobody complex, which can form a C 2 -symmetric, higher-order complex. Using local refinement, we determined high-resolution structures of the interfaces between apoB100 and LDLR. One binding interface is formed between several small-ligand-binding modules of LDLR and a series of basic patches that are scattered along a β-belt formed by apoB100, encircling LDL. The other binding interface is formed between the β-propeller domain of LDLR and the N-terminal domain of apoB100. Our results reveal how both interfaces are involved in LDL dimer formation, and how LDLR cycles between LDL- and self-bound conformations. In addition, known mutations in either apoB100 or LDLR, associated with high levels of LDL-C, are located at the LDL-LDLR interface.

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  • Two separate reports in Nature detailed the crystal structures of ApoB and the LDLR ligand binding domain bound to ApoB.

    “Recently, two separate reports in Nature detailed the crystal structures of ApoB77 and the LDLR ligand binding domain bound to ApoB78.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [78]

  • In detailing the LDLR ligand binding domain bound to a β-belt in ApoB, the impact of specific Class II mutations associated with familial hypercholesterolemia can now be modeled and are highlighted in structural diagrams.

    “In detailing the LDLR ligand binding domain bound to a β-belt in ApoB, the impact of specific Class II mutations associated with FH can now be modeled and are in fact highlighted in structural diagrams reported in one of the studies78.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [78]

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Research works printed but not linked: 66

  1. Segrest, J. P., Jones, M. K., De Loof, H. & Dashti, N. Structure of apolipoprotein B-100 in low density lipoproteins. J. Lipid Res. 42, 1346–1367 (2001). · DOI
  2. Suryawanshi, Y. N. & Warbhe, R. A. Familial hypercholesterolemia: a literature review of the pathophysiology and current and novel treatments. Cureus 15, e49121 (2023).
  3. Yu, Y. et al. Polyhedral 3D structure of human plasma very low density lipoproteins by individual particle cryo-electron tomography1. J. Lipid Res. 57, 1879–1888 (2016). · DOI
  4. Ehrlich, M. et al. Endocytosis by random initiation and stabilization of clathrin-coated pits. Cell 118, 591–605 (2004). · DOI · Paper page
  5. Rudenko, G. et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science 298, 2353–2358 (2002). · DOI · Paper page
  6. Jeon, H. & Blacklow, S. C. Structure and physiologic function of the low-density lipoprotein receptor. Annu. Rev. Biochem. 74, 535–562 (2005). · DOI · Paper page
  7. Mhaimeed, O. et al. The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: lower for longer is better. Am. J. Prev. Cardiol. 18, 100649 (2024). · DOI
  8. Chora, J. R., Medeiros, A. M., Alves, A. C. & Bourbon, M. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet. Med. 20, 591–598 (2018). · DOI
  9. Blacklow, S. C. Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers. Curr. Opin. Struct. Biol. 17, 419–426 (2007). · DOI · Paper page
  10. Wu, X. & Rapoport, T. A. Cryo-EM structure determination of small proteins by nanobody-binding scaffolds (Legobodies). Proc. Natl Acad. Sci. USA 118, e2115001118 (2021). · DOI
  11. Nykjaer, A. & Willnow, T. E. The low-density lipoprotein receptor gene family: a cellular Swiss army knife. Trends Cell Biol. 12, 273–280 (2002). · DOI
  12. Ren, G. et al. Model of human low-density lipoprotein and bound receptor based on cryoEM. Proc. Natl Acad. Sci. USA 107, 1059–1064 (2010). · DOI
  13. Kumar, V. et al. Three-dimensional cryoEM reconstruction of native LDL particles to 16Å resolution at physiological body temperature. PLoS One 6, e18841 (2011). · DOI
  14. Cisse, A. et al. Targeting structural flexibility in low density lipoprotein by integrating cryo-electron microscopy and high-speed atomic force microscopy. Int. J. Biol. Macromol. 252, 126345 (2023). · DOI
  15. Li, H. et al. Construction of a biotinylated cameloid-like antibody for lable-free detection of apolipoprotein B-100. Biosens. Bioelectron. 64, 111–118 (2015). · DOI
  16. Jeiran, K. et al. A new structural model of apolipoprotein B100 based on computational modeling and cross linking. Int. J. Mol. Sci. 23, 11480 (2022). · DOI
  17. Thompson, J. R. & Banaszak, L. J. Lipid–protein interactions in lipovitellin. Biochemistry 41, 9398–9409 (2002). · DOI
  18. Biterova, E. I. et al. The crystal structure of human microsomal triglyceride transfer protein. Proc. Natl Acad. Sci. USA 116, 17251–17260 (2019). · DOI
  19. Huang, R. et al. Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma. Nat. Struct. Mol. Biol. 18, 416–422 (2011). · DOI
  20. Esser, V., Limbird, L. E., Brown, M. S., Goldstein, J. L. & Russell, D. W. Mutational analysis of the ligand binding domain of the low density lipoprotein receptor. J. Biol. Chem. 263, 13282–13290 (1988). · DOI · Paper page
  21. Russell, D. W., Brown, M. S. & Goldstein, J. L. Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins. J. Biol. Chem. 264, 21682–21688 (1989). · DOI · Paper page
  22. Boren, J. et al. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J. Clin. Invest. 101, 1084–1093 (1998). · DOI
  23. Motazacker, M. M. et al. Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia. Eur. Heart J. 33, 1360–1366 (2012). · DOI
  24. Rodríguez-Jiménez, C. et al. Identification and functional analysis of APOB variants in a cohort of hypercholesterolemic patients. Int. J. Mol. Sci. 24, 7635 (2023). · DOI
  25. Fernández-Higuero, J. A. et al. Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing familial hypercholesterolaemia provides novel insights into variant pathogenicity. Sci. Rep. 5, 18184 (2015). · DOI
  26. Gaffney, D. et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 15, 1025–1029 (1995). · DOI
  27. Pullinger, C. R. et al. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. J. Clin. Invest. 95, 1225–1234 (1995). · DOI
  28. Huang, S., Henry, L., Ho, Y. K., Pownall, H. J. & Rudenko, G. Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor. J. Lipid Res. 51, 297–308 (2010). · DOI
  29. Gomez, A. et al. Functional analysis of six uncharacterised mutations in LDLR gene. Atherosclerosis 291, 44–51 (2019). · DOI
  30. Benito-Vicente, A. et al. The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia. Genet. Med. 17, 980–988 (2015). · DOI
  31. Duskova, L. et al. Low density lipoprotein receptor variants in the beta-propeller subdomain and their functional impact. Front. Genet. 11, 691 (2020). · DOI
  32. Wang, M. et al. Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia. Mol. Biol. Rep. 51, 153 (2024). · DOI
  33. Shen, H. et al. Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the Old Order Amish. Arch. Intern. Med. 170, 1850–1855 (2010). · DOI
  34. Soria, L. F. et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc. Natl Acad. Sci. USA 86, 587–591 (1989). · DOI
  35. Montasser, M. E. et al. Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen. Science 374, 1221–1227 (2021). · DOI
  36. Zhao, Y. et al. In-depth mass spectrometry analysis reveals the plasma proteomic and N-glycoproteomic impact of an Amish-enriched cardioprotective variant in B4GALT1. Mol. Cell. Proteomics 22, 100595 (2023). · DOI
  37. Zou, P. & Ting, A. Y. Imaging LDL receptor oligomerization during endocytosis using a co-internalization assay. ACS Chem. Biol. 6, 308–313 (2011). · DOI
  38. van Driel, I. R., Davis, C. G., Goldstein, J. L. & Brown, M. S. Self-association of the low density lipoprotein receptor mediated by the cytoplasmic domain. J. Biol. Chem. 262, 16127–16134 (1987). · DOI · Paper page
  39. Heymann, J. B. et al. Clathrin-coated vesicles from brain have small payloads: a cryo-electron tomographic study. J. Struct. Biol. 184, 43–51 (2013). · DOI
  40. Berndsen Z. T. & Cassidy, C. K. The structure of ApoB100 from human low-density lipoprotein. Preprint at bioRxiv https://doi.org/10.1101/2024.02.28.582555 (2024). · DOI · Paper page
  41. Lu, M. & Gursky, O. Aggregation and fusion of low-density lipoproteins in vivo and in vitro. Biomol. Concepts 4, 501–518 (2013). · DOI
  42. Öörni, K. & Kovanen, P. T. Aggregation susceptibility of low-density lipoproteins—a novel modifiable biomarker of cardiovascular risk. J. Clin. Med. 10, 1769 (2021). · DOI
  43. Maruyama, I. N. Activation of transmembrane cell-surface receptors via a common mechanism? The “rotation model”. Bioessays 37, 959–967 (2015). · DOI
  44. Feixas, F., Lindert, S., Sinko, W. & McCammon, J. A. Exploring the role of receptor flexibility in structure-based drug discovery. Biophys. Chem. 186, 31–45 (2014). · DOI · Paper page
  45. Heuser, J. E. & Anderson, R. G. Hypertonic media inhibit receptor-mediated endocytosis by blocking clathrin-coated pit formation. J. Cell Biol. 108, 389–400 (1989). · DOI
  46. Beglova, N., Jeon, H., Fisher, C. & Blacklow, S. C. Cooperation between fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor. Mol. Cell 16, 281–292 (2004). · DOI
  47. Havel, R. J., Eder, H. A. & Bragdon, J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J. Clin. Invest. 34, 1345–1353 (1955). · DOI
  48. Schumaker, V. N. & Puppione, D. L. Sequential flotation ultracentrifugation. Methods Enzymol. 128, 155–170 (1986). · DOI
  49. Gaubatz, J. W. et al. Dynamics of dense electronegative low density lipoproteins and their preferential association with lipoprotein phospholipase A2. J. Lipid Res. 48, 348–357 (2007). · DOI
  50. Banerjee, S. et al. Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake. Sci. Rep. 9, 11416 (2019). · DOI · Paper page
  51. Yost, S. A., Whidby, J., Khan, A. G., Wang, Y. & Marcotrigiano, J. Overcoming challenges of hepatitis C virus envelope glycoprotein production in mammalian cells. Methods Mol. Biol. 1911, 305–316 (2019). · DOI
  52. Wu, D. & Piszczek, G. Standard protocol for mass photometry experiments. Eur. Biophys. J. 50, 403–409 (2021). · DOI
  53. Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017). · DOI · Paper page
  54. Bepler, T. et al. Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs. Nat. Methods 16, 1153–1160 (2019). · DOI
  55. Cardone, G., Heymann, J. B. & Steven, A. C. One number does not fit all: mapping local variations in resolution in cryo-EM reconstructions. J. Struct. Biol. 184, 226–236 (2013). · DOI
  56. Sanchez-Garcia, R. et al. DeepEMhancer: a deep learning solution for cryo-EM volume post-processing. Commun. Biol. 4, 874 (2021). · DOI
  57. Jakobi, A. J., Wilmanns, M. & Sachse, C. Model-based local density sharpening of cryo-EM maps. eLife 6, e27131 (2017). · DOI
  58. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010). · DOI · Paper page
  59. Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D 75, 861–877 (2019). · DOI · Paper page
  60. Williams, C. J. et al. MolProbity: more and better reference data for improved all-atom structure validation. Protein Sci. 27, 293–315 (2018). · DOI · Paper page
  61. Wessel, D. & Flugge, U. I. A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal. Biochem. 138, 141–143 (1984). · DOI
  62. Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007). · DOI · Paper page
  63. Mendes, M. L. et al. An integrated workflow for crosslinking mass spectrometry. Mol. Syst. Biol. 15, e8994 (2019).
  64. Lenz, S. et al. Reliable identification of protein-protein interactions by crosslinking mass spectrometry. Nat. Commun. 12, 3564 (2021). · DOI · Paper page
  65. Kong, A. T., Leprevost, F. V., Avtonomov, D. M., Mellacheruvu, D. & Nesvizhskii, A. I. MSFragger: ultrafast and comprehensive peptide identification in mass spectrometry-based proteomics. Nat. Methods 14, 513–520 (2017). · DOI
  66. da Veiga Leprevost, F. et al. Philosopher: a versatile toolkit for shotgun proteomics data analysis. Nat. Methods 17, 869–870 (2020). · DOI

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Metadata

Authors
Reimund, M., Dearborn, A. D., Graziano, G., Lei, H., Ciancone, A. M., Kumar, A., Holewinski, R., Neufeld, E. B., O’Reilly, F. J., Remaley, A. T., & Marcotrigiano, J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-12-11
Volume
638
Issue
8051
Pages
829-835
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/s41586-024-08223-0
Cited by
63
References
2
Language
en
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