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PreprintCited by 43Protein Structure and DynamicsAdvanced Electron Microscopy Techniques and ApplicationsEnzyme Structure and Function

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The Structure of ApoB100 from Human Low-density Lipoprotein

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Berndsen, Zachary T., Cassidy, C. Keith·2024·Nature
DOI 10.1101/2024.02.28.582555PMC PMC11839476

Preprint — published as 10.1038/s41586-024-08467-w · Paper page

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Abstract

Low-density lipoprotein (LDL) plays a central role in lipid and cholesterol metabolism and is a key molecular agent involved in the development and progression of atherosclerosis, a leading cause of mortality worldwide. Apolipoprotein B100 (apoB100), one of the largest proteins in the genome, is the primary structural and functional component of LDL, yet its size and complex lipid associations have posed major challenges for structural studies. Here we overcome those challenges and present the first structure of apoB100 from human LDL using an integrative approach of cryo-electron microscopy, AlphaFold2, and molecular dynamics-based refinement. The structure consists of a large globular N-terminal domain that leads into a ∼58 nm long x 4 nm wide continuous amphipathic β-sheet that wraps completely around the circumference of the particle, holding it together like a belt. Distributed symmetrically across the two sides of the β-belt are 9 strategically located inserts that vary in size from ∼30-700 residues and appear to have diverse functions. The largest two form long flexible strings of paired amphipathic helices that extend across the lipid surface to provide additional structural support through specific long-range interactions. These results suggest a mechanism for how the various domains of apoB100 act in concert to maintain LDL shape and cohesion across a wide range of particle sizes. More generally, they advance our fundamental understanding of LDL form and function and will help accelerate the design of potential new therapeutics.

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Research works printed but not linked: 96

  1. 10.1007/s00249-008-0368-y · DOI
  2. 10.1371/journal.pone.0194797 · DOI
  3. 10.1194/jlr.R200004-JLR200 · DOI · Paper page
  4. 10.1038/323738a0 · DOI
  5. 1986, The complete cDNA and amino acid sequence of human apolipoprotein B-100, J Biol Chem, 261, 12918, 10.1016/S0021-9258(18)69248-8 · DOI
  6. 10.1093/eurheartj/ehx144 · DOI · Paper page
  7. 10.1007/s40119-018-0123-0 · DOI
  8. 10.1016/j.atherosclerosis.2021.05.016 · DOI
  9. 10.1373/clinchem.2004.038026 · DOI · Paper page
  10. 2020, Genetics of Familial Hypercholesterolemia: New Insights, Front Genet, 11, 574474, 10.3389/fgene.2020.574474 · DOI
  11. 10.1021/bi0354738 · DOI
  12. 10.1371/journal.pone.0018841 · DOI
  13. 10.1194/jlr.M070375 · DOI
  14. 2019, Single-molecule 3D imaging of human plasma intermediate-density lipoproteins reveals a polyhedral structure, Biochim Biophys Acta Mol Cell Biol Lipids, 1864, 260
  15. 2023, Targeting structural flexibility in low density lipoprotein by integrating cryo-electron microscopy and high-speed atomic force microscopy, Int J Biol Macromol, 252, 126345, 10.1016/j.ijbiomac.2023.126345 · DOI
  16. 10.1073/pnas.0908004107 · DOI
  17. 10.1194/jlr.M013946 · DOI
  18. 10.1021/acs.chemrev.1c00837 · DOI
  19. 2022, Forty years in cryoEM of membrane proteins, Microscopy (Oxf), 71, i30
  20. 10.1126/science.abm9326 · DOI · Paper page
  21. 2022, Model building of protein complexes from intermediate-resolution cryo-EM maps with deep learning-guided automatic assembly, Nat Commun, 13, 4066, 10.1038/s41467-022-31748-9 · DOI
  22. 10.1016/j.ymeth.2016.01.009 · DOI
  23. 10.1016/j.ymeth.2009.04.005 · DOI
  24. 10.1126/science.170681 · DOI
  25. 2017, Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases, Oxid Med Cell Longev, 2017, 1273042, 10.1155/2017/1273042 · DOI
  26. 10.1073/pnas.94.23.12291 · DOI
  27. 2000, Apolipoprotein A-I: structure-function relationships, J Lipid Res, 41, 853, 10.1016/S0022-2275(20)32028-9 · DOI
  28. 10.1016/j.jmb.2004.09.017 · DOI
  29. Jeiran, K. , et al., A New Structural Model of Apolipoprotein B100 Based on Computational Modeling and Cross Linking. Int J Mol Sci, 2022. 23(19). · DOI
  30. 10.1016/0022-2836(88)90542-6 · DOI
  31. 10.1042/bj2551057 · DOI
  32. 10.1097/01.mol.0000169353.12772.eb · DOI
  33. 10.1074/jbc.273.9.5196 · DOI
  34. 10.1074/jbc.274.5.3159 · DOI
  35. 10.1097/00041433-199908000-00008 · DOI
  36. 1999, N-terminal domain of apolipoprotein B has structural homology to lipovitellin and microsomal triglyceride transfer protein: a “lipid pocket” model for self-assembly of apob-containing lipoprotein particles, J Lipid Res, 40, 1401, 10.1016/S0022-2275(20)33382-4 · DOI
  37. 10.1021/bi025674w · DOI
  38. 10.1073/pnas.1903029116 · DOI
  39. 10.1529/biophysj.104.046235 · DOI
  40. 10.1002/pro.3235 · DOI · Paper page
  41. 10.1074/jbc.M406302200 · DOI
  42. 10.1021/bi011757l · DOI
  43. 10.1074/jbc.273.52.35216 · DOI
  44. 10.1074/jbc.271.31.18445 · DOI
  45. 1992, Lipoprotein assembly. Apolipoprotein B size determines lipoprotein core circumference, J Biol Chem, 267, 14839, 10.1016/S0021-9258(18)42116-3 · DOI
  46. 10.1073/pnas.0602213103 · DOI
  47. 1996, Differences in LDL subspecies involve alterations in lipid composition and conformational changes in apolipoprotein B, J Lipid Res, 37, 1924, 10.1016/S0022-2275(20)37557-X · DOI · Paper page
  48. 2001, Structure of apolipoprotein B-100 in low density lipoproteins, J Lipid Res, 42, 1346, 10.1016/S0022-2275(20)30267-4 · DOI
  49. 10.1073/pnas.0803626105 · DOI
  50. 1989, The use of monoclonal antibodies to localize the low density lipoprotein receptor-binding domain of apolipoprotein B, J Biol Chem, 264, 19754, 10.1016/S0021-9258(19)47176-7 · DOI
  51. 2018, Identification of Receptor Ligands in Apo B100 Reveals Potential Functional Domains, Protein J, 37, 548, 10.1007/s10930-018-9792-8 · DOI
  52. 10.1038/323734a0 · DOI
  53. 10.1016/S0006-291X(86)80287-X · DOI
  54. 1987, Human apolipoprotein B-100 heparin-binding sites, J Biol Chem, 262, 11097, 10.1016/S0021-9258(18)60931-7 · DOI
  55. 10.1172/JCI1847 · DOI
  56. 1995, Purification of the apolipoprotein B-67-containing low density lipoprotein particle and its affinity for the low density lipoprotein receptor, J Lipid Res, 36, 2622, 10.1016/S0022-2275(20)41098-3 · DOI
  57. 10.3390/f6082571 · DOI
  58. 1977, Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins, J Biol Chem, 252, 7279, 10.1016/S0021-9258(19)66966-8 · DOI
  59. 1995, Presence of an extended duplication in the putative low-density-lipoprotein receptor-binding domain of apolipoprotein B. Cloning and characterization of the domain in salmon, Eur J Biochem, 230, 45, 10.1111/j.1432-1033.1995.tb20532.x · DOI
  60. 10.1146/annurev.cellbio.1.1.1 · DOI
  61. 1984, Low-density lipoprotein receptor binding determinants switch from apolipoprotein E to apolipoprotein B during conversion of hypertriglyceridemic very-low-density lipoprotein to low-density lipoproteins, J Biol Chem, 259, 14728, 10.1016/S0021-9258(17)42663-9 · DOI
  62. 10.1161/01.ATV.20.5.1301 · DOI
  63. 10.1161/01.ATV.16.6.794 · DOI
  64. 1998, Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity, J Lipid Res, 39, 1263, 10.1016/S0022-2275(20)32551-7 · DOI
  65. 2022, Small dense low-density lipoprotein particles: clinically relevant?, Curr Opin Lipidol, 33, 160, 10.1097/MOL.0000000000000824 · DOI
  66. 10.1016/0006-291X(86)91083-1 · DOI
  67. 10.1161/01.ATV.14.10.1674 · DOI
  68. 1995, Immunoelectron microscopy of low density lipoproteins yields a ribbon and bow model for the conformation of apolipoprotein B on the lipoprotein surface, J Lipid Res, 36, 2027, 10.1016/S0022-2275(20)41120-4 · DOI
  69. 2000, Morphology of sodium deoxycholate-solubilized apolipoprotein B-100 using negative stain and vitreous ice electron microscopy, J Lipid Res, 41, 1464, 10.1016/S0022-2275(20)33459-3 · DOI
  70. 10.1126/science.3659919 · DOI
  71. 10.1016/0092-8674(87)90510-1 · DOI
  72. 2022, Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics, Signal Transduct Target Ther, 7, 265, 10.1038/s41392-022-01125-5 · DOI · Paper page
  73. 2022, Dietary management of dyslipidemia and the impact of dietary patterns on lipid disorders, Prog Cardiovasc Dis, 75, 49, 10.1016/j.pcad.2022.11.003 · DOI
  74. 2008, Common and rare gene variants affecting plasma LDL cholesterol, Clin Biochem Rev, 29, 11
  75. 2016, Familial defective apolipoprotein B-100: A review, J Clin Lipidol, 10, 1297, 10.1016/j.jacl.2016.09.009 · DOI
  76. 2017, Molecular basis of familial hypercholesterolemia, Curr Opin Cardiol, 32, 262, 10.1097/HCO.0000000000000385 · DOI
  77. 10.1194/jlr.R300002-JLR200 · DOI
  78. 1996, Positive linear correlation between the length of truncated apolipoprotein B and its secretion rate: in vivo studies in human apoB-89, apoB-75, apoB-54.8, and apoB-31 heterozygotes, J Lipid Res, 37, 844, 10.1016/S0022-2275(20)37582-9 · DOI
  79. 10.1172/JCI115799 · DOI
  80. Ji, E. and S. Lee , Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases. Int J Mol Sci, 2021. 22(11). · DOI
  81. 2003, SerialEM: A Program for Automated Tilt Series Acquisition on Tecnai Microscopes Using Prediction of Specimen Position, Microscopy and Microanalysis, 9, 1182, 10.1017/S1431927603445911 · DOI
  82. 2017, cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination, Nature methods, 14, 290, 10.1038/nmeth.4169 · DOI · Paper page
  83. 10.1002/PRO.3943 · DOI
  84. Mirdita, M. , et al., ColabFold: making protein folding accessible to all. Nature Methods, 2022: p. 1--4. · DOI · Paper page
  85. 10.1080/00268976.2013.813594 · DOI · Paper page
  86. 2019, Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix, Acta Crystallographica Section D: Structural Biology, 75, 861, 10.1107/S2059798319011471 · DOI · Paper page
  87. 2018, ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps, Acta Crystallogr D Struct Biol, 74, 519, 10.1107/S2059798318002425 · DOI
  88. 10.1016/0263-7855(96)00018-5 · DOI · Paper page
  89. 10.1002/jcc.20084 · DOI
  90. 10.1002/jcc.20289 · DOI · Paper page
  91. 2020, Scalable molecular dynamics on CPU and GPU architectures with NAMD, J Chem Phys, 153, 044130, 10.1063/5.0014475 · DOI
  92. 10.1002/jcc.23354 · DOI
  93. 10.1093/bioinformatics/btr168 · DOI
  94. 2021, ProDy 2.0: increased scale and scope after 10 years of protein dynamics modelling with Python, Bioinformatics, 37, 3657, 10.1093/bioinformatics/btab187 · DOI
  95. 2023, UniProt Tools: BLAST, Align, Peptide Search, and ID Mapping, Curr Protoc, 3, e697, 10.1002/cpz1.697 · DOI
  96. 10.1093/bioinformatics/btp033 · DOI

Metadata

Authors
Berndsen, Z. T., & Cassidy, C. K.
Affiliations
University of Missouri (US)
Corresponding author
  • Berndsen, Zachary T.
  • Cassidy, C. Keith
ORCID
Venue
Nature
Publisher
openRxiv
Published
2024-03-01
Volume
638
Issue
8051
Pages
836-843
ISSN
0028-0836 (ISSN-L)
DOI
10.1101/2024.02.28.582555
PMC
PMC11839476
OpenAlex
W4405268548
Cited by
43
References
1
Citations by year
2026: 22 · 2025: 19 · 2024: 2
FWCI
5.85
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Nature (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
University of Missouri
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
apolipoprotein B-100, low-density lipoprotein, protein structure, intramolecular cross-links, protein-lipid interactions, atherosclerosis, cholesterol metabolism
MeSH terms
Protein Domains, Protein Conformation, beta-Strand, Humans, Lipoproteins, LDL, Models, Molecular, Cryoelectron Microscopy, Apolipoprotein B-100, Molecular Dynamics Simulation

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