In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor

Structure of lipid bilayers

http://europepmc.org/articles/PMC1300937?pdf=render

Effect of Chain Length and Unsaturation on Elasticity of Lipid Bilayers

Vesicles consisting of a bilayer membrane of amphiphilic lipid molecules are remarkably flexible surfaces that show an amazing variety of shapes of different symmetry and topology. Owing to the fluidity of the membrane, shape transitions such as budding can be induced by temperature changes or the action of optical tweezers. Thermally excited shape fluctuations are both strong and slow enough to be visible by video microscopy. Depending on the physical conditions, vesicles adhere to and unbind from each other or a substrate. This article describes the systematic physical theory developed to understand the static and dynamic aspects of membrane and vesicle configurations. The preferred shapes arise from a competition between curvature energy, which derives from the bending elasticity of the membrane, geometrical constraints such as fixed surface area and fixed enclosed volume, and a signature of the bilayer aspect. These shapes of lowest energy are arranged into phase diagrams, which separate regi...

Configurations of fluid membranes and vesicles

The hydrated synthetic lecithins, dimyristoyl and dipalmitoyllecithins, undergo two thermal transitions, a broad low enthalpy "pretransition" prior to the sharp first-order "chain-melting" transition. Both phospholipids exhibit the same temperature-dependent structural changes associated with the thermal pretransition. At low temperatures, below the pretransition, a one-dimensional lamellar lattice is observed. The hydrocarbon chains are fully extended and tilted with respect to the plane of the lipid bilayer. The hydrocarbon chain packing displays a temperature dependence and the angle of tilt of the hydrocarbon chains decreases with increasing temperature, reaching a minimum value of 30 degrees at the pretransition temperature of both lecithins. The pretransition is associated with a structural transformation from a one-dimensional lamellar to a two-dimensional monoclinic lattice consisting of lipid lamellae distorted by a periodic ripple. The hydrocarbon chains remain tilted in the temperature range intermediate between the pretransition and chain-melting transition. The cell parameters of this two-dimensional lattice exhibit a compositional dependence. The a parameter (proportional to the lamellar repeat distance) increases with increasing water content, while the b parameter (a measure of the ripple periodicity) decreases with increasing water content. At the chain-melting transition, the hydrocarbon chains of the phospholipid melt and assume a liquid-like conformation and the lattice reverts to one-dimensional lamellar. These structural changes observed for dimyristoyl- and dipalmitoyllecithins may be a common feature of all synthetic lecithins exhibiting a thermal pretransition. The appearance of the pretransition and accompanying two-dimensional may arise from specific interactions between the choline moiety of the polar head group and the structured water matrix surrounding it.

Nature of the Thermal pretransition of synthetic phospholipids: dimyristolyl- and dipalmitoyllecithin.

Temperature and compositional dependence of the structure of hydrated dimyristoyl lecithin.

Structure and interactions of lipids in human plasma low density lipoproteins.

The three-dimensional crystal structure of cholera toxin.

Crystals of 1,2 dilauroyl-DL-phosphatidyl-ethanolamine:acetic acid are monoclinic with a = 462, b = 777, c = 995 A, β = 920°; space group P21/c The structural analysis, based on the visual estimates of 1467 reflection intensities, was achieved by direct methods, and least squares analysis convergence was to R1 = 028 There are marked differences between the observed molecular conformation and those that have been predicted theoretically The mean planes containing the lipid chains are essentially parallel to one another; the phosphodiester moiety has a double gauche conformation, while intermolecular hydrogen bonding modifies the conformation that could be anticipated for an isolated phosphatidylethanolamine molecule The intermolecular packing produces the classical lipid bilayer structure, adjacent lipid bilayers being separated by acetic acid molecules of crystallization The hydrocarbon chain packing can be considered either as a quasi-hexagonal type or as a complex orthorhombic subcell arrangement One-dimensional electron density profiles across the lipid bilayer at increasing resolution clearly demonstrate the origin of features present on the low resolution profiles of both model and natural membranes

https://www.pnas.org/content/pnas/71/8/3036.full.pdf

G. Graham Shipley

Papers

Nature of the Thermal pretransition of synthetic phospholipids: dimyristolyl- and dipalmitoyllecithin.

Temperature and compositional dependence of the structure of hydrated dimyristoyl lecithin.

Structure and interactions of lipids in human plasma low density lipoproteins.

The three-dimensional crystal structure of cholera toxin.

Structural Chemistry of 1,2 Dilauroyl-DL-phosphatidylethanolamine: Molecular Conformation and Intermolecular Packing of Phospholipids