Cholesterol as a co‐solvent and a ligand for membrane proteins

Abstract

Charles Sanders is the co-recipient of the Protein Society 2013 Hans Neurath Award.Abstract: As of mid 2013 a Medline search on "cholesterol" yielded over 200,000 hits, reflecting the prominence of this lipid in numerous aspects of animal cell biology and physiology under conditions of health and disease. Aberrations in cholesterol homeostasis underlie both a number of rare genetic disorders and contribute to common sporadic and complex disorders including heart disease, stroke, type II diabetes, and Alzheimer's disease. The corresponding author of this review and his lab stumbled only recently into the sprawling area of cholesterol research when they discovered that the amyloid precursor protein (APP) binds cholesterol, a topic covered by the Hans Neurath Award lecture at the 2013 Protein Society Meeting. Here, we first provide a brief overview of cholesterol-protein interactions and then offer our perspective on how and why binding of cholesterol to APP and its C99 domain (b-CTF) promotes the amyloidogenic pathway, which is closely related to the etiology of Alzheimer's disease.

APOE ε4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage

“…Given the central role of lipids in cellular membrane trafficking and integrity, these represent areas of great interest for further investigation into the basic pathophysiology of nonlobar ICH. 19,20 Ultimately, additional studies will be required to confirm and expand our findings.…”

G protein coupled receptor interactions with cholesterol deep in the membrane

“…G protein-coupled receptors (GPCRs) in mammalian cells are located in a membrane, the plasma membrane, rich in cholesterol with cholesterol making up between 25 and 50 mol % of the lipid in the membrane [1]. Crystal structures of some, but not all, GPCRs crystallized from cubic phases or detergent micelles containing cholesterol or cholesterol hemisuccinate show small numbers of resolved molecules of sterol bound to the GPCR surface [2][3][4][5][6][7].…”

“…A number of cholesterol-binding motifs have been identified, including the CCM, CRAC and CARC motifs, all involving hydrogen bonding to the cholesterol -OH group, but many resolved cholesterol molecules are not bound at any of these motifs and many examples of the motifs are not occupied by resolved cholesterol molecules [1,8,9]. In fact, full atomistic and coarse-grained molecular dynamics (MD) simulations of GPCRs in cholesterol-containing bilayers suggest that cholesterol molecules are not localised in well-defined deep energy wells on the protein surface but, rather, occupy a more or less continuous range of positions of similar energy, covering most of the membrane-spanning region of the GPCR [10][11][12][13].…”

“…5 The fact that cholesterol contains only a single polar group makes it more hydrophobic than a phospholipid; the calculated free energy of partition for a cholesterol monomer between water and hydrocarbon is comparable to that of an alcohol of C20 chain length [16]. As a consequence, although most cholesterol molecules in a membrane are located with their -OH groups in the headgroup region of the lipid bilayer with their hydrophobic ring systems more or less perpendicular to the plane of the membrane [1], a proportion of the cholesterol molecules occupy positions with their -OH groups deep within the fatty acyl chain region of the bilayer, close to the bilayer centre, as shown by neutron diffraction studies and full atomistic and coarse-grained molecular dynamic simulations and consistent with the reported high rate of flip-flop of cholesterol across the membrane [17][18][19][20].…”

Stimulation, Inhibition, or Stabilization of Na,K-ATPase Caused by Specific Lipid Interactions at Distinct Sites

“…(Fig. 7), unlike stimulation by polyunsaturated PE or PC, and it is well established that cholesterol forms strong interactions with saturated fatty acyl chains, especially of SM (53,62), the SM/cholesterol is a likely inhibitory pair in native membranes.…”