Molecular Determinants of Cholesterol Binding to Soluble and Transmembrane Protein Domains

  • Jessica Ounjian
  • Anna N. Bukiya
  • Avia Rosenhouse-DantskerEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1135)


Cholesterol-protein interactions play a critical role in lipid metabolism and maintenance of cell integrity. To elucidate the molecular mechanisms underlying these interactions, a growing number of studies have focused on determining the crystal structures of a variety of proteins complexed with cholesterol. These include structures in which cholesterol binds to transmembrane domains, and structures in which cholesterol interacts with soluble ones. However, it remains unknown whether there are differences in the prerequisites for cholesterol binding to these two types of domains. Thus, to define the molecular determinants that characterize the binding of cholesterol to these two distinct protein domains, we employed the database of crystal structures of proteins complexed with cholesterol. Our analysis suggests that cholesterol may bind more strongly to soluble domains than to transmembrane domains. The interactions between cholesterol and the protein in both cases critically depends on hydrophobic and aromatic residues. In addition, cholesterol binding sites in both types of domains involve polar and/or charged residues. However, the percentage of appearance of the different types of polar/charged residues in cholesterol binding sites differs between soluble and transmembrane domains. No differences were observed in the conformational characteristics of the cholesterol molecules bound to soluble versus transmembrane protein domains suggesting that cholesterol is insensitive to the environment provided by the different protein domains.


Cholesterol binding Soluble domain Transmembrane domain Lipid-protein interactions Steroid binding site 



Cholesterol recognition motif exhibiting an inverted CRAC orientation along the polypeptide chain


Cholesterol Consensus Motif


Cholesterol Recognition Amino acid Consensus (motif)


Niemann-Pick Type C (protein)


Protein Data Bank


Research Collaboratory for Structural Bioinformatics


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Jessica Ounjian
    • 1
  • Anna N. Bukiya
    • 2
  • Avia Rosenhouse-Dantsker
    • 1
    Email author
  1. 1.Department of ChemistryUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of PharmacologyThe University of Tennessee HSCMemphisUSA

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