https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(06)00153-2.pdf

Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.

A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor.

The translocator protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders.

Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders

The plasma membrane of eukaryotic cells contains several types of lipids displaying high biochemical variability in both their apolar moiety (e.g. the acyl chain of glycerolipids) and their polar head (e.g. the sugar structure of glycosphingolipids). Among these lipids, cholesterol is unique because its biochemical variability is almost exclusively restricted to the oxidation of its polar -OH group. Although generally considered the most rigid membrane lipid, cholesterol can adopt a broad range of conformations due to the flexibility of its isooctyl chain linked to the polycyclic sterane backbone. Moreover, cholesterol is an asymmetric molecule displaying a planar face and a rough  face. Overall, these structural features open up a number of possible interactions between cholesterol and membrane lipids and proteins, consistent with the prominent regulatory functions that this unique lipid exerts on membrane components. The aim of this review is to describe how cholesterol interacts with membrane lipids and proteins at the molecular/atomic scale, with special emphasis on transmembrane domains of proteins containing either the consensus cholesterol-binding motifs CRAC and CARC or a tilted peptide. Despite their broad structural diversity, all these domains bind cholesterol through common molecular mechanisms, leading to the identification of a subset of amino acid residues that are overrepresented in both linear and three-dimensional membrane cholesterol-binding sites.

/pdf/how-cholesterol-interacts-with-membrane-proteins-an-4fbhlpho06.pdf

How cholesterol interacts with membrane proteins: an exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains

Steroid hormones regulate diverse physiological functions such as reproduction, blood salt balance, maintenance of secondary sexual characteristics, response to stress, neuronal function and various metabolic processes. They are synthesized from cholesterol mainly in the adrenal gland and gonads in response to tissue-specific tropic hormones. These steroidogenic tissues are unique in that they require cholesterol not only for membrane biogenesis, maintenance of membrane fluidity and cell signaling, but also as the starting material for the biosynthesis of steroid hormones. It is not surprising, then, that cells of steroidogenic tissues have evolved with multiple pathways to assure the constant supply of cholesterol needed to maintain optimum steroid synthesis. The cholesterol utilized for steroidogenesis is derived from a combination of sources: 1) de novo synthesis in the endoplasmic reticulum (ER); 2) the mobilization of cholesteryl esters (CEs) stored in lipid droplets through cholesteryl ester hydrolase; 3) plasma lipoprotein-derived CEs obtained by either LDL receptor-mediated endocytic and/or SR-BI-mediated selective uptake; and 4) in some cultured cell systems from plasma membrane-associated free cholesterol. Here, we focus on recent insights into the molecules and cellular processes that mediate the uptake of plasma lipoprotein-derived cholesterol, events connected with the intracellular cholesterol processing and the role of crucial proteins that mediate cholesterol transport to mitochondria for its utilization for steroid hormone production. In particular, we discuss the structure and function of SR-BI, the importance of the selective cholesterol transport pathway in providing cholesterol substrate for steroid biosynthesis and the role of two key proteins, StAR and PBR/TSO in facilitating cholesterol delivery to inner mitochondrial membrane sites, where P450scc (CYP11A) is localized and where the conversion of cholesterol to pregnenolone (the common steroid precursor) takes place.

/pdf/cellular-cholesterol-delivery-intracellular-processing-and-3eut3holrx.pdf

Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones.

We previously defined a cholesterol recognition/interaction amino acid consensus sequence [CRAC: L/V–X (1–5)–Y–X (1–5)-R/K] in the carboxyl terminus of the peripheral-type benzodiazepine receptor (PBR), a high-affinity drug and cholesterol-binding protein present in the outer mitochondrial membrane protein. This protein is involved in the regulation of cholesterol transport into the mitochondria, the rate-determining step in steroid biosynthesis. Reconstituted wild-type recombinant PBR into proteoliposomes demonstrated high-affinity 2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide and cholesterol binding. In the present work, we functionally and structurally characterized this CRAC motif using reconstituted recombinant PBR and nuclear magnetic resonance. Deletion of the C-terminal domain of PBR and mutation of the highly conserved among all PBR amino acid sequences Y152 of the CRAC domain resulted in loss of the ability of mutant recPBR to bind cholesterol. Nuclear magnetic resonance...

/pdf/characterization-of-the-cholesterol-recognition-amino-acid-4bj9gcpw34.pdf

Characterization of the cholesterol recognition amino acid consensus sequence of the peripheral-type benzodiazepine receptor.

Existence and Stability of Periodic and Almost Periodic Solutions to the Boussinesq System in Unbounded Domains

Stability and periodicity of solutions to Navier-Stokes equations on non-compact riemannian manifolds with negative curvature

Considering the evolution equations of parabolic type on a non-compact Einstein manifold $(\mathcal M,g)$ with negative Ricci curvature tensor, we establish results on the existence, uniqueness of time-periodic (on the time half-axis) and almost periodic 

Periodic and almost periodic evolution flows and their stability on non-compact Einstein manifolds and applications

Motivated by the Lp−Lq smoothing properties of heat semigroups on unbounded domains and the conditional stability of hyperbolic semigroups, we develop a unified approach toward the problems on the existence of periodic solutions to the evolution equation u˙=Au(t)+Bg(u)(t). Our method is based on the analysis of (X,Y,φ)-stability of the semigroup (T(t))t≥0 generated by A, i.e. ‖T(t)x‖Y⩽φ(t)‖x‖X, t>0, for certain couple of Banach spaces (X,Y) and real-valued function φ satisfying limt→∞φ(t)=0. Our theory covers both cases corresponding to Lp−Lq smoothing properties and the conditional stability of hyperbolic semigroups as well as some other important situations relating to the polynomial or exponential stability of semigroups. As illustrations for our theory, we give applications to the existence and uniqueness of periodic solutions to Navier–Stokes and damped wave equations. 

Thi Kim Ngoc Vu

Papers

Characterization of the cholesterol recognition amino acid consensus sequence of the peripheral-type benzodiazepine receptor.

Existence and Stability of Periodic and Almost Periodic Solutions to the Boussinesq System in Unbounded Domains

Stability and periodicity of solutions to Navier-Stokes equations on non-compact riemannian manifolds with negative curvature

Periodic and almost periodic evolution flows and their stability on non-compact Einstein manifolds and applications

(X,Y,φ)-Stable semigroups, periodic solutions, and applications