Skip to main content
SpringerLink
Log in

Modes of Cholesterol Binding in Membrane Proteins: A Joint Analysis of 73 Crystal Structures

  • Chapter
  • First Online:
Direct Mechanisms in Cholesterol Modulation of Protein Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1135))

Abstract

Cholesterol is a highly asymmetric lipid molecule. As an essential constituent of the cell membrane, cholesterol plays important structural and signaling roles in various biological processes. The first high-resolution crystal structure of a transmembrane protein in complex with cholesterol was a human β2-adrenergic receptor structure deposited to the Protein Data Bank in 2007. Since then, the number of the cholesterol-bound crystal structures has grown considerably providing an invaluable resource for obtaining insights into the structural characteristics of cholesterol binding. In this work, we examine the spatial and orientation distributions of cholesterol relative to the protein framework in a collection of 73 crystal structures of membrane proteins. To characterize the cholesterol-protein interactions, we apply singular value decomposition to an array of interatomic distances, which allows us to systematically assess the flexibility and variability of cholesterols in transmembrane proteins. Together, this joint analysis reveals the common characteristics among the observed cholesterol structures, thereby offering important guidelines for prediction and modification of potential cholesterol binding sites in transmembrane proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CARC:

Inverted CRAC

CCM:

Cholesterol consensus motif

CLR:

Cholesterol

CRAC:

Cholesterol recognition amino acid consensus

GPCR:

G-protein coupled receptor

PDB:

Protein Data Bank

RMSD:

Root mean square deviation

SVD:

Singular value decomposition

TM:

Transmembrane

VDW:

van del Waals

References

  1. Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol. 2008;9(2):125–38.

    Article  CAS  PubMed  Google Scholar 

  2. Yeagle PL. Modulation of membrane function by cholesterol. Biochimie. 1991;73(10):1303–10.

    Article  CAS  PubMed  Google Scholar 

  3. Yeagle PL. Cholesterol and the cell membrane. Biochim Biophys Acta. 1985;822(3–4):267–87.

    Article  CAS  PubMed  Google Scholar 

  4. Maxfield FR, van Meer G. Cholesterol, the central lipid of mammalian cells. Curr Opin Cell Biol. 2010;22(4):422–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sheng R, et al. Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins. Nat Commun. 2012;3:1249.

    Article  PubMed  Google Scholar 

  6. Ramprasad OG, et al. Changes in cholesterol levels in the plasma membrane modulate cell signaling and regulate cell adhesion and migration on fibronectin. Cell Motil Cytoskeleton. 2007;64(3):199–216.

    Article  CAS  PubMed  Google Scholar 

  7. Goluszko P, Nowicki B. Membrane cholesterol: a crucial molecule affecting interactions of microbial pathogens with mammalian cells. Infect Immun. 2005;73(12):7791–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gimpl G, Burger K, Fahrenholz F. Cholesterol as modulator of receptor function†. Biochemistry. 1997;36(36):10959–74.

    Article  CAS  PubMed  Google Scholar 

  9. Rosenhouse-Dantsker A, Mehta D, Levitan I. Regulation of ion channels by membrane lipids. In: Terjung R, editor. Comprehensive physiology. Hoboken, NJ: John Wiley & Sons, Inc.; 2012. https://doi.org/10.1002/cphy.c110001.

    Chapter  Google Scholar 

  10. Cherezov V, et al. High-resolution crystal structure of an engineered human b2-adrenergic G protein–coupled receptor. Science. 2007;318(5854):1258–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rosenbaum DM, et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science. 2007;318:9.

    Google Scholar 

  12. Morth JP, et al. Crystal structure of the sodium–potassium pump. Nature. 2007;450(7172):1043–9.

    Article  CAS  PubMed  Google Scholar 

  13. Hanson MA, et al. A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor. Structure. 2008;16(6):897–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shinoda T, Ogawa H, Cornelius F, Toyoshima C. Crystal structure of the sodium–potassium pump at 2.4 Å resolution. Nature. 2009;459(7245):446–50.

    Article  CAS  PubMed  Google Scholar 

  15. Liu W, et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012;337(6091):232–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wada T, et al. Crystal structure of the eukaryotic light-driven proton-pumping rhodopsin, acetabularia rhodopsin II, from marine alga. J Mol Biol. 2011;411(5):986–98.

    Article  CAS  PubMed  Google Scholar 

  17. Liu W, et al. Serial femtosecond crystallography of G protein–coupled receptors. Science. 2013;342:5.

    Google Scholar 

  18. Penmatsa A, Wang KH, Gouaux E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature. 2013;503(7474):85–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu H, et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014;344(6179):58–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang K, et al. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature. 2014;509(7498):115–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Burg JS, et al. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science. 2015;347(6226):1113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang D, et al. Two disparate ligand-binding sites in the human P2Y1 receptor. Nature. 2015;520(7547):317–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Penmatsa A, Wang KH, Gouaux E. X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine. Nat Struct Mol Biol. 2015;22(6):506–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang W, et al. Structural insights into μ-opioid receptor activation. Nature. 2015;524(7565):315–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Coleman JA, Green EM, Gouaux E. X-ray structures and mechanism of the human serotonin transporter. Nature. 2016;532(7599):334–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen Y, et al. Structure of the STRA6 receptor for retinol uptake. Science. 2016;353(6302):aad8266.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zimmerman B, et al. Crystal structure of a full-length human tetraspanin reveals a cholesterol-binding pocket. Cell. 2016;167(4):1041–1051.e11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oswald C, et al. Intracellular allosteric antagonism of the CCR9 receptor. Nature. 2016;540(7633):462–5.

    Article  CAS  PubMed  Google Scholar 

  29. Martin-Garcia JM, et al. Serial millisecond crystallography of membrane and soluble protein microcrystals using synchrotron radiation. IUCrJ. 2017;4(4):439–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cheng RKY, et al. Structures of human A 1 and A 2A adenosine receptors with xanthines reveal determinants of selectivity. Structure. 2017;25(8):1275–1285.e4.

    Article  CAS  PubMed  Google Scholar 

  31. Hua T, et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature. 2017;547(7664):468–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shihoya W, et al. X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. Nat Struct Mol Biol. 2017;24(9):758–64.

    Article  CAS  PubMed  Google Scholar 

  33. Johnson ZL, Chen J. ATP binding enables substrate release from multidrug resistance protein 1. Cell. 2018;172(1–2):81–89.e10.

    Article  CAS  PubMed  Google Scholar 

  34. Che T, et al. Structure of the nanobody-stabilized active state of the kappa opioid receptor. Cell. 2018;172(1–2):55–67.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jungnickel KEJ, Parker JL, Newstead S. Structural basis for amino acid transport by the CAT family of SLC7 transporters. Nat Commun. 2018;9(1):550. https://doi.org/10.1038/s41467-018-03066-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang Z, Tóth B, Szollosi A, Chen J, Csanády L. Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation. eLife. 2018;7:e36409. https://doi.org/10.7554/eLife.36409.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Epand RM. Cholesterol and the interaction of proteins with membrane domains. Prog Lipid Res. 2006;45(4):279–94.

    Article  CAS  PubMed  Google Scholar 

  38. Li H, Papadopoulos V. Peripheral-type benzodiazepine receptor function in cholesterol transport. Identification of a putative cholesterol recognition/interaction amino acid sequence and consensus pattern. Endocrinology. 1998;139(12):7.

    Article  Google Scholar 

  39. Fantini J, Barrantes FJ. How cholesterol interacts with membrane proteins: an exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains. Front Physiol. 2013;4:31. https://doi.org/10.3389/fphys.2013.00031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Braun W. Distance geometry and related methods for protein structure determination from NMR data. Q Rev Biophys. 1987;19(3–4):115.

    Article  CAS  PubMed  Google Scholar 

  41. Ren Z. Molecular events during translocation and proofreading extracted from 200 static structures of DNA polymerase. Nucleic Acids Res. 2016;44(15):7457–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. DeLano WL. Pymol: an open-source molecular graphics tool. CCP4 Newslet Protein Crystal. 2002;40:82–92.

    Google Scholar 

  43. Adams PD, et al. PHENIX: a comprehensive python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010;66(2):213–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kinoshita M, Okada T. Structural conservation among the rhodopsin-like and other G protein-coupled receptors. Sci Rep. 2015;5(1) https://doi.org/10.1038/srep09176.

  45. Ren Z. Reverse engineering the cooperative machinery of human hemoglobin. PLoS One. 2013;8(11):e77363.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA

    Cong Wang, Arthur Ralko, Zhong Ren, Avia Rosenhouse-Dantsker & Xiaojing Yang

  2. Department of Ophthalmology and Vision Sciences, University of Illinois at Chicago, Chicago, IL, USA

    Xiaojing Yang

Authors
  1. Cong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arthur Ralko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhong Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Avia Rosenhouse-Dantsker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaojing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaojing Yang .

Editor information

Editors and Affiliations

  1. Department of Chemistry, University of Illinois, Chicago, IL, USA

    Avia Rosenhouse-Dantsker

  2. Department of Pharmacology, The University of Tennessee HSC, Memphis, TN, USA

    Anna N. Bukiya

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wang, C., Ralko, A., Ren, Z., Rosenhouse-Dantsker, A., Yang, X. (2019). Modes of Cholesterol Binding in Membrane Proteins: A Joint Analysis of 73 Crystal Structures. In: Rosenhouse-Dantsker, A., Bukiya, A. (eds) Direct Mechanisms in Cholesterol Modulation of Protein Function. Advances in Experimental Medicine and Biology, vol 1135. Springer, Cham. https://doi.org/10.1007/978-3-030-14265-0_4

Download citation

Publish with us

Policies and ethics

Search

Navigation