BBA - Molecular and Cell Biology of Lipids (v.1771, #6)
Editorial Board (ii).
Special issue: Lipid transporters in cell biology by Shamshad Cockcroft (641-643).
CERT and intracellular trafficking of ceramide by Kentaro Hanada; Keigo Kumagai; Nario Tomishige; Miyuki Kawano (644-653).
The transport and sorting of lipids from the sites of their synthesis to their appropriate destinations are fundamental for membrane biogenesis. In the synthesis of sphingolipids in mammalian cells, ceramide is newly produced at the endoplasmic reticulum (ER), and transported from the ER to the trans Golgi regions, where it is converted to sphingomyelin. CERT has been identified as a key factor for the ER-to-Golgi trafficking of ceramide. CERT contains several functional domains including (i) a START domain capable of catalyzing inter-membrane transfer of ceramide, (ii) a pleckstrin homology domain, which serves to target the Golgi apparatus by recognizing phosphatidylinositol 4-monophosphate, and (iii) a short peptide motif named FFAT motif which interacts with the ER-resident membrane protein VAP. CERT is preferentially distributed to the Golgi region in cells, and Golgi-targeted CERT appears to retain the activity to interact with VAP. On the basis of these results, it has been proposed that CERT extracts ceramide from the ER and carries it to the Golgi apparatus in a non-vesicular manner and that a particularly efficient cycle of CERT movement for trafficking of ceramide may proceed at membrane contact sites between the ER and the Golgi apparatus.
Keywords: PH domain; START domain; FFAT motif; Membrane contact sites;
Structure and function of phosphatidylcholine transfer protein (PC-TP)/StarD2 by Keishi Kanno; Michele K. Wu; Erez F. Scapa; Steven L. Roderick; David E. Cohen (654-662).
Phosphatidylcholine transfer protein (PC-TP) is a highly specific soluble lipid binding protein that transfers phosphatidylcholine between membranes in vitro. PC-TP is a member of the steroidogenic acute regulatory protein-related transfer (START) domain superfamily. Although its biochemical properties and structure are well characterized, the functions of PC-TP in vivo remain incompletely understood. Studies of mice with homozygous disruption of the Pctp gene have largely refuted the hypothesis that this protein participates in the hepatocellular selection and transport of biliary phospholipids, in the production of lung surfactant, in leukotriene biosynthesis and in cellular phosphatidylcholine metabolism. Nevertheless, Pctp −/− mice exhibit interesting defects in lipid homeostasis, the understanding of which should elucidate the biological functions of PC-TP.
Keywords: Phospholipid; Cholesterol; Triglyceride; Lipid transfer protein; Steroidogenic acute regulatory protein-related transfer (START) domain; Peroxisome proliferator activated receptor α;
Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter by Walter L. Miller (663-676).
Cholesterol is a vital component of cellular membranes, and is the substrate for biosynthesis of steroids, oxysterols and bile acids. The mechanisms directing the intracellular trafficking of this nearly insoluble molecule have received increased attention through the discovery of the steroidogenic acute regulatory protein (StAR) and similar proteins containing StAR-related lipid transfer (START) domains. StAR can transfer cholesterol between synthetic liposomes in vitro, an activity which appears to correspond to the trans-cytoplasmic transport of cholesterol to mitochondria. However, trans-cytoplasmic cholesterol transport in vivo appears to involve the recently-described protein StarD4, which is expressed in most cells. Steroidogenic cells must also move large amounts of cholesterol from the outer mitochondrial membrane to the first steroidogenic enzyme, which lies on the matrix side of the inner membrane; this action requires StAR. Congenital lipoid adrenal hyperplasia, a rare and severe disorder of human steroidogenesis, results from mutations in StAR, providing a StAR knockout of nature that has provided key insights into its activity. Cell biology experiments show that StAR moves large amounts of cholesterol from the outer to inner mitochondrial membrane, but acts exclusively on the outer membrane. Biophysical data show that only the carboxyl-terminal α-helix of StAR interacts with the outer membrane. Spectroscopic data and molecular dynamics simulations show that StAR's interactions with protonated phospholipid head groups on the outer mitochondrial membrane induce a conformational change (molten globule transition) needed for StAR's activity. StAR appears to act in concert with the peripheral benzodiazepine receptor, but the precise itinerary of a cholesterol molecule entering the mitochondrion remains unclear.
Keywords: Adrenal; Steroid; Molten globule; Membrane; Molecular dynamic;
Biochemical and biological functions of class I phosphatidylinositol transfer proteins by Shamshad Cockcroft; Nicolas Carvou (677-691).
Phosphoinositides function in a diverse array of cellular activities. They include a role as substrate for lipid kinases and phospholipases to generate second messengers, regulators of the cytoskeleton, of enzymes and of ion channels, and docking sites for reversible recruitment of proteins to membranes. Mammalian phosphatidylinositol transfer proteins, PITPα and PITPβ are paralogs that share 77% sequence identity and contain a hydrophobic cavity that can sequester either phosphatidylinositol or phosphatidylcholine. A string of 11 amino acid residues at the C-terminal acts as a “lid” which shields the lipid from the aqueous environment. PITPs in vitro can facilitate inter-membrane lipid transfer and this requires the movement of the “lid” to allow the lipid cargo to be released. Thus PITPs are structurally designed for delivering lipid cargo and could thus participate in cellular events that are dependent on phosphatidylinositol or derivatives of phosphatidylinositol. Phosphatidylinositol, the precursor for all phosphoinositides is synthesised at the endoplasmic reticulum and its distribution to other organelles could be facilitated by PITPs. Here we highlight recent studies that report on the three-dimensional structures of the different PITP forms and suggest how PITPs are likely to dock at the membrane surface for lipid delivery and extraction. Additionally we discuss whether PITPs are important regulators of sphingomyelin metabolism, and finally describe recent studies that link the association of PITPs with diverse functions including membrane traffic at the Golgi, neurite outgrowth, cytokinesis and stem cell growth.
Keywords: Sphingomyelin; Lipid transport; Golgi; Netrin-1; Cytokinesis; Phosphoinositide; Phospholipase C;
RdgB proteins: Functions in lipid homeostasis and signal transduction by Deepti Trivedi; Raghu Padinjat (692-699).
The RdgBs are a group of evolutionarily conserved molecules that contain a phosphatidylinositol transfer protein (PITP) domain. However in contrast to classical PITPs (PITPα) with whom they share the conserved PITP domain, these proteins also contain several additional sequence elements whose functional significance remains unknown. The founding member of the family DrdgBα (Drosophila rdgB) appears to be essential for sensory transduction and maintenance of ultra structure in photoreceptors (retinal sensory neurons). Although proposed to support the maintenance of phosphatidylinositol 4, 5 bisphosphate [PI (4, 5) P2] levels during G-protein coupled phospholipase C activity in these cells, the biochemical mechanism of DrdgBα function remains unresolved. More recently, a mammalian RdgB protein has been implicated in the maintenance of diacylglycerol (DAG) levels and secretory function at Golgi membranes. In this review we discuss existing work on the function of RdgB proteins and set out future challenges in understanding this group of lipid transfer proteins.
Keywords: RdgB; Retinal degeneration; Phosphatidylinositol; PI(4,5)P2; Diacylglycerol; Golgi; Drosophilia; Photoreceptors;
Sterol carrier protein-2: New roles in regulating lipid rafts and signaling by Friedhelm Schroeder; Barbara P. Atshaves; Avery L. McIntosh; Adalberto M. Gallegos; Stephen M. Storey; Rebecca D. Parr; John R. Jefferson; Judith M. Ball; Ann B. Kier (700-718).
Sterol carrier protein-2 (SCP-2) was independently discovered as a soluble protein that binds and transfers cholesterol as well as phospholipids (nonspecific lipid transfer protein, nsLTP) in vitro. Physiological functions of this protein are only now beginning to be resolved. The gene encoding SCP-2 also encodes sterol carrier protein-x (SCP-x) arising from an alternate transcription site. In vitro and in vivo SCP-x serves as a peroxisomal 3-ketoacyl-CoA thiolase in oxidation of branched-chain lipids (cholesterol to form bile acids; branched-chain fatty acid for detoxification). While peroxisomal SCP-2 facilitates branched-chain lipid oxidation, the role(s) of extraperoxisomal (up to 50% of total) are less clear. Studies using transfected fibroblasts overexpressing SCP-2 and hepatocytes from SCP-2/SCP-x gene-ablated mice reveal that SCP-2 selectively remodels the lipid composition, structure, and function of lipid rafts/caveolae. Studies of purified SCP-2 and in cells show that SCP-2 has high affinity for and selectively transfers many lipid species involved in intracellular signaling: fatty acids, fatty acyl CoAs, lysophosphatidic acid, phosphatidylinositols, and sphingolipids (sphingomyelin, ceramide, mono-di-and multi-hexosylceramides, gangliosides). SCP-2 selectively redistributes these signaling lipids between lipid rafts/caveolae and intracellular sites. These findings suggest SCP-2 serves not only in cholesterol and phospholipid transfer, but also in regulating multiple lipid signaling pathways in lipid raft/caveolae microdomains of the plasma membrane.
Keywords: Caveolae; Lipid raft; Sterol carrier protein-2; SCP-2; Phosphatidylinositol; Sphingolipid; Cholesterol; Fatty acyl CoA; Fatty acid;
The lipid-binding SEC14 domain by Kan Saito; Lutz Tautz; Tomas Mustelin (719-726).
Protein–lipid interactions are important for protein targeting, signal transduction, lipid transport, lipid biosynthesis, lipid metabolism, and the maintenance of cellular compartments and membranes. Specific lipid-binding protein domains, such as PH, FYVE, PX, PHD, C2 and SEC14 homology domains, mediate interactions between proteins and specific phospholipids. Here we review the published literature, plus some of our most recent unpublished findings, regarding the biology of the SEC14 domain, also known as CRAL_TRIO domain.
Keywords: SEC14; CRAL_TRIO; CRAL_TRIO_N; PTP-MEG2; PTPN9; TAP; SEC14L; Trio; Dbl; Sec14p;
The Sec14-superfamily and the regulatory interface between phospholipid metabolism and membrane trafficking by Carl J. Mousley; Kimberly R. Tyeryar; Patrick Vincent-Pope; Vytas A. Bankaitis (727-736).
A central principle of signal transduction is the appropriate control of the process so that relevant signals can be detected with fine spatial and temporal resolution. In the case of lipid-mediated signaling, organization and metabolism of specific lipid mediators is an important aspect of such control. Herein, we review the emerging evidence regarding the roles of Sec14-like phosphatidylinositol transfer proteins (PITPs) in the action of intracellular signaling networks; particularly as these relate to membrane trafficking. Finally, we explore developing ideas regarding how Sec14-like PITPs execute biological function. As Sec14-like proteins define a protein superfamily with diverse lipid (or lipophile) binding capabilities, it is likely these under-investigated proteins will be ultimately demonstrated as a ubiquitously important set of biological regulators whose functions influence a large territory in the signaling landscape of eukaryotic cells.
Keywords: PITP; Membrane trafficking; Sec14p; PITPs; Lipids; Signaling; Genetics; Polarized membrane growth;
Sec14 related proteins in yeast by Peter Griac (737-745).
Lipid transport between membranes of eukaryotic organisms represents an essential aspect of organelle biogenesis. This transport must be strictly selective and directional to assure specific lipid composition of individual membranes. Despite the intensive research effort in the last few years, our understanding of how lipids are sorted and moved within cells is still rather limited. Evidence indicates that at least some of the mechanisms generating and maintaining non-random distribution of lipids in cells are linked to the action of phosphatidylinositol transfer proteins (PITPs). The major PITP in yeast Saccharomyces cerevisiae, Sec14p, is essential in promoting Golgi secretory function by modulating of its membrane lipid composition. This review focuses on a group of five yeast proteins that share significant sequence homology with Sec14p. Based on this sequence identity, they were termed Sfh (Sec fourteen homologue) proteins. It is a diverse group of proteins with distinct subcellular localizations and varied physiological functions related to lipid metabolism, phosphoinositide mediated signaling and membrane trafficking.
Keywords: Sfh proteins; Lipid transport; Saccharomyces cerevisiae; Sec14p; Phosphatidylinositol; Phosphatidylcholine;
Glycolipid transfer proteins by Rhoderick E. Brown; Peter Mattjus (746-760).
Glycolipid transfer proteins (GLTPs) are small (24 kDa), soluble, ubiquitous proteins characterized by their ability to accelerate the intermembrane transfer of glycolipids in vitro. GLTP specificity encompasses both sphingoid- and glycerol-based glycolipids, but with a strict requirement that the initial sugar residue be beta-linked to the hydrophobic lipid backbone. The 3D architecture of GLTP reveals liganded structures with unique lipid-binding modes. The biochemical properties of GLTP action at the membrane surface have been studied rather comprehensively, but the biological role of GLTP remains enigmatic. What is clear is that GLTP differs distinctly from other known glycolipid-binding proteins, such as nonspecific lipid transfer proteins, lysosomal sphingolipid activator proteins, lectins, lung surfactant proteins as well as other lipid-binding/transfer proteins. Based on the unique conformational architecture that targets GLTP to membranes and enables glycolipid binding, GLTP is now considered the prototypical and founding member of a new protein superfamily in eukaryotes.
Keywords: GLTP; Lipid transfer protein structure; Membrane interaction motif; Glycosphingolipid; HET-C2; ACD11; FAPP2; Cerebroside; Ganglioside; Sphingomyelin; Cholesterol; Phosphatidylcholine;
Lipid-transfer proteins in membrane trafficking at the Golgi complex by Maria Antonietta De Matteis; Antonella Di Campli; Giovanni D'Angelo (761-768).
The Golgi complex (GC) represents the central junction for membrane trafficking. Protein and lipid cargoes continuously move through the GC in both anterograde and retrograde directions, departing to and arriving from diverse destinations within the cell. Nevertheless, the GC is able to maintain its identity and strict compartmentalisation, having a different composition in terms of protein and lipid content compared to other organelles. The discovery of coat protein complexes and the elucidation of their role in sorting cargo proteins into specific transport carriers have provided a partial answer to this phenomenon. However, it is more difficult to understand how relatively small and diffusible molecules like lipids can be concentrated in or excluded from specific subcellular compartments. The discovery of lipid-transfer proteins operating in the secretory pathway and specifically at the GC has shed light on one possible way in which this lipid compartmentalisation can be accomplished. The correct lipid distribution along the secretory pathway is of crucial importance for cargo protein sorting and secretion. This review focuses on what is now known about the putative and effective lipid-transfer proteins at the GC, and on how they affect the function and structure of the GC itself.
Keywords: Golgi complex; FAPP; CERT; OSBP;
Sterol transport in yeast and the oxysterol binding protein homologue (OSH) family by Timothy A. Schulz; William A. Prinz (769-780).
Sterols such as cholesterol are a significant component of eukaryotic cellular membranes, and their unique physical properties influence a wide variety of membrane processes. It is known that the concentration of sterol within the membrane varies widely between organelles, and that the cell actively maintains this distribution through various transport processes. Vesicular pathways such as secretion or endocytosis may account for this traffic, but increasing evidence highlights the importance of nonvesicular routes as well. The structure of an oxysterol-binding protein homologue (OSH) in yeast (Osh4p/Kes1p) has recently been solved, identifying it as a sterol binding protein, and there is evidence consistent with the role of a cytoplasmic, nonvesicular sterol transporter. Yeast have seven such proteins, which appear to have distinct but overlapping functions with regard to maintaining intracellular sterol distribution and homeostasis. Control of sterol distribution can have far-reaching effects on membrane-related functions, and Osh proteins have been implicated in a variety of processes such as secretory vesicle budding from the Golgi and establishment of cell polarity. This review summarizes the current body of knowledge regarding this family and its potential functions, placing it in the context of known and hypothesized pathways of sterol transport in yeast.
Keywords: Yeast; Oxysterol binding protein; Sterol; Lipid; Membrane transport; Lipid binding protein;
Plant non-specific lipid transfer proteins: An interface between plant defence and human allergy by G. Salcedo; R. Sánchez-Monge; D. Barber; A. Díaz-Perales (781-791).
Plant non-specific LTPs (lipid transfer proteins) form a protein family of basic polypeptides of 9 kDa ubiquitously distributed throughout the plant kingdom. The members of this family are located extracellularly, usually associated with plant cell walls, and possess a broad lipid-binding specificity closely related to their three-dimensional structure. The nsLTP fold is characterized by a compact domain composed of 4 α-helices, firmly held by a network of 4 conserved disulphide bridges. This fold presents a large internal tunnel-like cavity, which can accommodate different types of lipids. nsLTPs are involved in plant defence mechanisms against phytopathogenic bacteria and fungi, and, possibly, in the assembly of hydrophobic protective layers of surface polymers, such as cutin. In addition, several members of the nsLTP family have been identified as relevant allergens in plant foods and pollens. Their high resistance to both heat treatment and digestive proteolytic attack has been related with the induction by these allergens of severe symptoms in many patients. Therefore, they are probably primary sensitizers by the oral route. nsLTP sensitization shows an unexpected pattern throughout Europe, with a high prevalence in the Mediterranean area, but a low incidence in Northern and Central European countries.
Keywords: Lipid transfer protein; Plant defence; Plant allergen; Food allergy; Panallergen family;