BBA - Molecular and Cell Biology of Lipids (v.1761, #8)
Editorial Board (ii).
Special issue: Lipid-binding domains by Wonhwa Cho (803-804).
Membrane binding domains by James H. Hurley (805-811).
Eukaryotic signaling and trafficking proteins are rich in modular domains that bind cell membranes. These binding events are tightly regulated in space and time. The structural, biochemical, and biophysical mechanisms for targeting have been worked out for many families of membrane binding domains. This review takes a comparative view of seven major classes of membrane binding domains, the C1, C2, PH, FYVE, PX, ENTH, and BAR domains. These domains use a combination of specific headgroup interactions, hydrophobic membrane penetration, electrostatic surface interactions, and shape complementarity to bind to specific subcellular membranes.
Keywords: Protein kinase C; Diacylglycerol; Phosphoinositide; Signal transduction; Membrane trafficking;
The role of electrostatics in protein–membrane interactions by Anna Mulgrew-Nesbitt; Karthikeyan Diraviyam; Jiyao Wang; Shaneen Singh; Paul Murray; Zhaohui Li; Laura Rogers; Nebojsa Mirkovic; Diana Murray (812-826).
Many experimental, structural and computational studies have established the importance of nonspecific electrostatics as a driving force for peripheral membrane association. Here we focus on this component of protein/membrane interactions by using examples ranging from phosphoinositide signaling to retroviral assembly. We stress the utility of the collaboration of experiment and theory in identifying and quantifying the role of electrostatics not only in contributing to membrane association, but also in affecting subcellular targeting, in the control of membrane binding, and in the organization of proteins and lipids at membrane surfaces.
Keywords: Peripheral protein; Electrostatics; Protein/membrane interaction; Phosphoinositide; Computational biology; Electrostatic switch; Lateral organization;
C1 domains exposed: From diacylglycerol binding to protein–protein interactions by Francheska Colón-González; Marcelo G. Kazanietz (827-837).
C1 domains, cysteine-rich modules originally identified in protein kinase C (PKC) isozymes, are present in multiple signaling families, including PKDs, chimaerins, RasGRPs, diacylglycerol kinases (DGKs) and others. Typical C1 domains bind the lipid second messenger diacylglycerol (DAG) and DAG-mimetics such as phorbol esters, and are critical for governing association to membranes. On the contrary, atypical C1 domains possess structural determinants that impede phorbol ester/DAG binding. C1 domains are generally expressed as twin modules (C1A and C1B) or single domains. Biochemical and cellular studies in PKC and PKD isozymes revealed that C1A and C1B domains are non-equivalent as lipid-binding motifs or translocation modules. It has been recently determined that individual C1 domains have unique patterns of ligand recognition, driven in some cases by subtle structural differences. Insights from recent 3-D studies on β2-chimaerin and Munc13-1 revealed that their single C1 domains are sterically blocked by intramolecular interactions, suggesting that major conformational changes would be required for exposing the site of DAG interaction. Thus, it is clear that the protein context plays a major role in determining whether binding of DAG to the C1 domain would lead to enzyme activation or merely serves as an anchoring mechanism.
Keywords: C1 domain; Diacylglycerol; Phorbol esters; Protein kinase C; Chimaerins;
Membrane binding and subcellular targeting of C2 domains by Wonhwa Cho; Robert V. Stahelin (838-849).
C2 domains are a ubiquitous structural module and many of them function in Ca2+-dependent membrane binding and thereby serve as Ca2+ effectors for divergent Ca2+-mediated cellular processes. Extensive structural, biochemical, biophysical, and cellular studies of C2 domains and host proteins in the past decade have shown that due to their structural diversity C2 domains have disparate Ca2+ sensitivity, lipid selectivity and membrane binding mechanisms. This review summarizes the basic structural and functional properties of C2 domains as well as recent findings on Ca2+ and membrane binding, lipid selectivity, and subcellular localization of C2 domains and their host proteins.
Keywords: C2 domain; Lipid; Membrane; Calcium; Signaling; Membrane trafficking; Subcellular localization;
Membrane and juxtamembrane targeting by PH and PTB domains by Jonathan P. DiNitto; David G. Lambright (850-867).
Modular pleckstrin homology (PH) and phospho-tyrosine binding (PTB) domains are present in a remarkably large number of proteins from yeast to humans. With a common core fold, these domain families have evolved to recognize membrane embedded phospholipids, in particular phosphoinositides, peripheral membrane proteins, and peptide motifs in juxtamembrane regions of integral membrane proteins. As the result of intensive investigation using biochemical, biophysical, and structural approaches, common ligand recognition principles have emerged along with insights into the structural variations that account for the diversity of ligand specificities. Analyses of membrane targeting in cells have revealed additional determinants beyond the primary ligand binding sites. In this review, we highlight unifying recognition principles and further illustrate with examples how divergent mechanisms contribute to membrane and juxtamembrane targeting by PH and PTB domains.
Phosphatidylinositol 3-phosphate recognition and membrane docking by the FYVE domain by Tatiana G. Kutateladze (868-877).
The FYVE domain is a small zinc binding module that recognizes phosphatidylinositol 3-phosphate [PtdIns(3)P], a phospholipid enriched in membranes of early endosomes and other endocytic vesicles. It is usually present as a single module or rarely as a tandem repeat in eukaryotic proteins involved in a variety of biological processes including endo- and exocytosis, membrane trafficking and phosphoinositide metabolism. A number of FYVE domain-containing proteins are recruited to endocytic membranes through the specific interaction of their FYVE domains with PtdIns(3)P. Structures and PtdIns(3)P binding modes of several FYVE domains have recently been characterized, shedding light on the molecular basis underlying multiple cellular functions of these proteins. Here, structural and functional aspects and the current mechanism of the multivalent membrane anchoring by monomeric or dimeric FYVE domain are reviewed. This mechanism involves stereospecific recognition of PtdIns(3)P that is facilitated by non-specific electrostatic contacts and modulated by the histidine switch, and is accompanied by hydrophobic insertion. Contributions of each component to the FYVE domain specificity and affinity for PtdIns(3)P-containing membranes are discussed.
Keywords: FYVE domain; Phosphoinositide; Phosphatidylinositol 3-phosphate; Membrane; Endosome;
The Phox (PX) domain proteins and membrane traffic by Li-Fong Seet; Wanjin Hong (878-896).
Phosphoinositides (PIs) are phosphorylated derivatives of phosphatidylinositol (PtdIns) that regulate many cellular and physiological processes. Most PIs act by serving as membrane docking sites for proteins harboring specific PI-binding domains so that the location and function of these proteins could be dynamically governed. The Phox (PX) domain represents a novel PI-binding module capable of regulating membrane targeting of about 47 mammalian proteins, 30 of which are tentatively referred to as sorting nexins (SNXs). Some SNXs have been implicated in regulating membrane trafficking in the endocytic pathway. We discuss here recent development and progress in the study of the PX domain-containing proteins.
Keywords: PX domain; Phosphoinositide; Lipid; Endosome; Membrane targeting; Membrane traffic; Endocytosis;
BAR, F-BAR (EFC) and ENTH/ANTH domains in the regulation of membrane–cytosol interfaces and membrane curvature by Toshiki Itoh; Pietro De Camilli (897-912).
BAR and ENTH domains are families of α-helical lipid bilayer binding modules found in proteins that function in endocytosis, actin regulation and signaling. Several members of these families not only bind the bilayer, but also participate in the regulation of its curvature. These properties are thought to play physiological roles at sites of membrane budding and at other sites where narrow tubular membranes occur in vivo. Studies of BAR and ENTH domains and of their flanking regions have provided new insights into mechanisms of membrane deformation and curvature sensing, and have emphasized the importance of amphipathic helices, thought to intercalate in one of the leaflets of the lipid bilayer, in the generation of membrane curvature. Structural studies and database searches are rapidly expanding the BAR and ENTH domains families, with the identification of new related domains and subfamilies, such as F-BAR (also called EFC) domains and ANTH domains, respectively. Here we present a short overview of the properties of these domains based on evidence obtained from genetics, cell biology, biochemistry and structural biology.
Keywords: PCH family; EFC domain; FCH domain; IMD domain; Dynamin; Clathrin; N-WASP; Tubulation; Actin; Endocytosis;
Phosphatidic acid- and phosphatidylserine-binding proteins by Catherine L. Stace; Nicholas T. Ktistakis (913-926).
Phosphatidic acid and phosphatidylserine are negatively charged abundant phospholipids with well-recognized structural roles in cellular membranes. They are also signaling lipids since their regulated formation (or appearance) can constitute an important signal for downstream responses. The list of potential effectors for these lipids is expanding rapidly and includes proteins involved in virtually all aspects of cellular regulation. Because it is not always clear whether these effectors recognize the specific phospholipids or a general negatively-charged membrane environment, questions about specificity must be addressed on a case by case basis. In this review we present an up to date list of potential phosphatidic acid- and phosphatidylserine-binding proteins.
Keywords: Lipid signaling; Phosphatidic acid; Phosphatidylserine; Lipid recognition; Phospholipase D;
Sphingolipid-binding proteins by C.F. Snook; J.A. Jones; Y.A. Hannun (927-946).
Emerging information on sphingolipid metabolism and signaling is leading to a better understanding of cellular processes such as apoptosis, cancer, cell survival and aging. In this review, we discuss the involvement of sphingolipids in these processes and focus on underlying mechanisms based on sphingolipid:protein interactions. Due to the inherent difficulty of studying lipids, we discuss techniques that are useful in the elucidation of these interactions. We classify sphingolipid-binding proteins into four main classes: receptor, effector, enzyme, and transporter. Known structures of sphingolipid-binding proteins are surveyed, and sphingolipid-binding characteristics are described, acknowledging the limitations that there are presently insufficient protein:sphingolipid complexes for more definitive conclusions on this topic. Finally we summarize relevant literature to better inform the reader about sphingolipid:protein interactions.
Keywords: Sphingosine; Ceramide; Sphingosine 1-phosphate; Ceramide 1-phosphate; Sphingolipid; Glycosphingolipid; Sphingomyelinase; CERT;
The prevalence and significance of PDZ domain–phosphoinositide interactions by Pascale Zimmermann (947-956).
PDZ domains predominate in multi-cellular organisms. They are ubiquitous protein-interaction modules recognizing short peptide sequences generally situated at the C-terminal end of plasma membrane proteins. They contribute to the formation and spatial confinement of protein complexes and thereby play an essential role in the control of cell signaling. Recent studies indicate that PDZ domains can also interact with phosphoinositides (PIPs), signaling lipids with key-roles in receptor signal transduction, membrane trafficking, cytoskeleton remodeling and nuclear processes. In particular the PDZ domains of syntenin-1 and syntenin-2 bind to phosphatidylinositol 4, 5-bisphosphate (PIP2) with high-affinity. Syntenin-1/PIP2 interaction is important for receptor cargo recycling and syntenin-2 plays a role in the organization of nuclear PIP2. In addition, other lower-affinity PDZ domain/PIPs interactions are documented. Here, we summarize and discuss the present knowledge about the occurrence, the biochemistry and the biology of PDZ domain–lipid interactions.
Keywords: PDZ; Lipid; Biosensor; Scaffolding; Trafficking; Nucleus;
Live cell imaging of phosphoinositide dynamics with fluorescent protein domains by Péter Várnai; Tamas Balla (957-967).
Phosphoinositides make up only a small fraction of membrane phospholipids yet they are of outmost significance in regulating membrane-associated signaling processes. A large number of inositol lipid kinases and phosphatases have evolved to control the rapid production and elimination of these lipids at specific cellular membrane compartments. For a long period of time, the only information about the spatial aspect of inositol lipid metabolism relied upon the immunostaining of enzymes or cell fractionation of the enzyme activities that acted upon these lipids. Recent advances in the understanding of the nature of protein–inositol lipid interactions permitted the design of fluorescent molecular probes that can interact with inositol lipids in a specific manner allowing imaging of phosphoinositide dynamics in live cells. This approach has rapidly gained high popularity, but also provoked criticisms and debate about its limitations. In this review, we will summarize our experience with using these molecular tools and address some issues that most often come up in discussions concerning the usefulness and drawbacks of this technique. The most important value of these debates is that they also challenge our preconceived views of how phosphoinositides regulate cellular functions.
Keywords: Green fluorescent protein; Phosphoinositide; Pleckstrin homology domain; InsP3; Calcium; Phospholipase C;