Lipids Protein–lipid interactions on the surfaces of cell...
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425 Addresses Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, and Regional Primate Research Center, University of Washington, Seattle, WA 98195, USA; e-mail: [email protected] Current Opinion in Structural Biology 1999, 9:425–427 http://biomednet.com/elecref/0959440X00900425 © Elsevier Science Ltd ISSN 0959-440X Abbreviations Gla γ-carboxyglutamate i-face interfacial binding surface The three reviews in this section relate to the peripheral membrane proteins of mammalian cells. These proteins are the focus of an important, emerging field in structural biology. It’s already clear that they are quite diverse and include cytoskeletal proteins [1], the coat proteins of secre- tory and endocytic vesicles [2], protein kinases [3], GTP-binding proteins [4] and the enzymes and lipid trans- port proteins that contribute to lipid-dependent cell signaling [5,6]. Furthermore, evidence is accumulating that they bind to the lipids of cell membranes by different mechanisms. For example, some of the proteins contain pleckstrin homology domains that bind phosphoinositides [7], others contain C2 domains that bind membrane lipids in the presence of Ca 2+ [8], others contain positively charged regions that bind to negatively charged phospho- glycerides [9] and others contain covalently attached fatty acyl groups or prenyl groups that anchor them to mem- branes [4,10]. Beyond this, adjacent membrane lipids that do not bind proteins directly may modulate the protein–lipid interactions [11], the binding of proteins to membrane surfaces may promote further changes in the structure and function of the proteins [12] and groups of proteins that bind to the same membrane surface may interact with each other to effect complex membrane responses (e.g. [13]). In view of this complexity, several key questions have to be considered for each protein–lipid interaction. What region of the protein is involved in membrane binding and what specific amino acids in the region form the interfacial binding surface (i-face)? Which membrane lipids interact with the amino acids and what types of intermolecular contacts are involved? Does the targeting of the protein to a membrane depend solely on these lipids or does it also depend on an interaction with a membrane protein? Does protein–lipid binding have additional structural effects on the protein or on adjacent membrane lipids and proteins? How are the protein’s interactions with membrane lipids and proteins regulated? To answer questions like these for even a sin- gle, peripheral membrane protein would be a major task, so the challenge for the field as a whole is clear. The review by Gelb, Cho and Wilton (pp 428–432) sum- marizes initial attempts to address this challenge for secreted members of the phospholipase A 2 enzyme superfamily. In particular, the authors focus on the i-faces of these enzymes, which are of special interest because of the correlation between different amino acid composi- tions and differences in the enzymes’ ability to interact with model lipid surfaces. For example, the i-face of a secreted phospholipase A 2 from the pancreas contains several basic amino acids that interact electrostatically with model lipid surfaces that contain negatively charged phosphoglycerides. Similar interactions may be of func- tional importance in vivo, because the enzyme normally catalyzes the hydrolysis of ingested phosphoglycerides that are present in mixed micelles and emulsions that also contain conjugated bile acids. Other phospholipase A 2 enzymes secreted by mammalian cells are thought to bind to cell plasma membranes during inflammatory responses. Gelb, Cho and Wilton point out that the i-face of one of these enzymes contains a tryptophan residue that promotes hydrophobic interactions between the enzyme and phosphatidylcholine-containing model membranes. Importantly, the same tryptophan residue was found to influence the enzyme’s ability to promote the release of free fatty acids and leukotriene B4 from cultured cells [14]. Thus, even in the case of secreted phospholipase A 2 enzymes that are otherwise closely related, differences in i-face structure correlate with dif- ferences in the mode of attachment to lipid surfaces and may also correlate with differences in function. The secreted phospholipase A 2 enzymes act extracellular- ly in the presence of millimolar concentrations of Ca 2+ and have phosphoglyceride-substrate-binding pockets that contain one bound Ca 2+ ion required for catalysis [15,16]; however, they do not show Ca 2+ -dependent binding to model membranes. Only one type of phospholipase A 2 is known to show such binding. It is a cytosolic enzyme that binds to intracellular membranes in response to Ca 2+ sig- nals and catalyzes the preferential release of arachidonic acid from membrane phosphoglycerides [5]. The enzyme contains a C2 domain that binds two Ca 2+ ions between three connecting loops of an antiparallel β sandwich [17]. The bound Ca 2+ ions are thought to promote protein–lipid interactions by stabilizing a hydrophobic lipid-binding region on two of the loops [18–22]. Lipids Protein–lipid interactions on the surfaces of cell membranes Editorial overview John A Glomset
Transcript of Lipids Protein–lipid interactions on the surfaces of cell...
425
AddressesHoward Hughes Medical Institute, Departments of Medicine andBiochemistry, and Regional Primate Research Center, University ofWashington, Seattle, WA 98195, USA;e-mail: [email protected]
Current Opinion in Structural Biology 1999, 9:425–427
http://biomednet.com/elecref/0959440X00900425
© Elsevier Science Ltd ISSN 0959-440X
AbbreviationsGla γ-carboxyglutamatei-face interfacial binding surface
The three reviews in this section relate to the peripheralmembrane proteins of mammalian cells. These proteinsare the focus of an important, emerging field in structuralbiology. It’s already clear that they are quite diverse andinclude cytoskeletal proteins [1], the coat proteins of secre-tory and endocytic vesicles [2], protein kinases [3],GTP-binding proteins [4] and the enzymes and lipid trans-port proteins that contribute to lipid-dependent cellsignaling [5,6]. Furthermore, evidence is accumulatingthat they bind to the lipids of cell membranes by differentmechanisms. For example, some of the proteins containpleckstrin homology domains that bind phosphoinositides[7], others contain C2 domains that bind membrane lipidsin the presence of Ca2+ [8], others contain positivelycharged regions that bind to negatively charged phospho-glycerides [9] and others contain covalently attached fattyacyl groups or prenyl groups that anchor them to mem-branes [4,10]. Beyond this, adjacent membrane lipids thatdo not bind proteins directly may modulate theprotein–lipid interactions [11], the binding of proteins tomembrane surfaces may promote further changes in thestructure and function of the proteins [12] and groups ofproteins that bind to the same membrane surface mayinteract with each other to effect complex membraneresponses (e.g. [13]).
In view of this complexity, several key questions have tobe considered for each protein–lipid interaction. Whatregion of the protein is involved in membrane bindingand what specific amino acids in the region form theinterfacial binding surface (i-face)? Which membranelipids interact with the amino acids and what types ofintermolecular contacts are involved? Does the targetingof the protein to a membrane depend solely on theselipids or does it also depend on an interaction with amembrane protein? Does protein–lipid binding haveadditional structural effects on the protein or on adjacentmembrane lipids and proteins? How are the protein’s
interactions with membrane lipids and proteinsregulated? To answer questions like these for even a sin-gle, peripheral membrane protein would be a major task,so the challenge for the field as a whole is clear.
The review by Gelb, Cho and Wilton (pp 428–432) sum-marizes initial attempts to address this challenge forsecreted members of the phospholipase A2 enzymesuperfamily. In particular, the authors focus on the i-facesof these enzymes, which are of special interest because ofthe correlation between different amino acid composi-tions and differences in the enzymes’ ability to interactwith model lipid surfaces. For example, the i-face of asecreted phospholipase A2 from the pancreas containsseveral basic amino acids that interact electrostaticallywith model lipid surfaces that contain negatively chargedphosphoglycerides. Similar interactions may be of func-tional importance in vivo, because the enzyme normallycatalyzes the hydrolysis of ingested phosphoglyceridesthat are present in mixed micelles and emulsions that alsocontain conjugated bile acids. Other phospholipase A2enzymes secreted by mammalian cells are thought tobind to cell plasma membranes during inflammatoryresponses. Gelb, Cho and Wilton point out that the i-faceof one of these enzymes contains a tryptophan residuethat promotes hydrophobic interactions between theenzyme and phosphatidylcholine-containing modelmembranes. Importantly, the same tryptophan residuewas found to influence the enzyme’s ability to promotethe release of free fatty acids and leukotriene B4 fromcultured cells [14]. Thus, even in the case of secretedphospholipase A2 enzymes that are otherwise closelyrelated, differences in i-face structure correlate with dif-ferences in the mode of attachment to lipid surfaces andmay also correlate with differences in function.
The secreted phospholipase A2 enzymes act extracellular-ly in the presence of millimolar concentrations of Ca2+ andhave phosphoglyceride-substrate-binding pockets thatcontain one bound Ca2+ ion required for catalysis [15,16];however, they do not show Ca2+-dependent binding tomodel membranes. Only one type of phospholipase A2 isknown to show such binding. It is a cytosolic enzyme thatbinds to intracellular membranes in response to Ca2+ sig-nals and catalyzes the preferential release of arachidonicacid from membrane phosphoglycerides [5]. The enzymecontains a C2 domain that binds two Ca2+ ions betweenthree connecting loops of an antiparallel β sandwich [17].The bound Ca2+ ions are thought to promote protein–lipidinteractions by stabilizing a hydrophobic lipid-bindingregion on two of the loops [18–22].
LipidsProtein–lipid interactions on the surfaces of cell membranesEditorial overviewJohn A Glomset
The three groups of proteins that are discussed in thereview by Nelsestuen and Ostrowski (pp 433–437) alsoshow Ca2+-dependent binding to lipid surfaces, but by dif-ferent mechanisms and with a considerably higher Ca2+
stoichiometry. The pentraxins are extracellular proteinsthat, like some of the secreted phospholipase A2 enzymes,are thought to contribute to inflammatory responses[23–25]. Ca2+ ions bind to the five subunits of each pen-traxin molecule and this can promote protein–lipidinteractions with negatively charged model membranes[26–29]. Nelsestuen and Ostrowski make the point thatpentraxins that have positively charged, Ca2+-containingi-faces bind to these membranes, whereas correspondingpentraxins that have negatively charged i-faces do not.This observation may be of biological relevance becausethe outer surfaces of damaged cells and activated plateletsare thought to contain relatively high amounts of phos-phatidylserine. On the other hand, human plasmaC-reactive protein, a pentraxin that does not show Ca2+-dependent binding to negatively charged modelmembranes, reportedly shows Ca2+-dependent bindingboth to model membranes that contain high amounts oflysophosphatidylcholine [30,31] and to cells that havebeen damaged by treatment with snake venom phospholi-pase A2 [31,32]. The basis for these effects remains to bedetermined, but human C-reactive protein is known tocontain a Ca2+-dependent binding site for the polar headgroup of phosphatidylcholine [28,29] and it has been spec-ulated that this binding site may be involved [25].
In contrast to pentraxins, annexins show Ca2+-dependentbinding to the cytosolic surfaces of cell membranes [33].Ca2+ ions bind to the i-face of each annexin [34] andNelsestuen and Ostrowski argue that this may promoteprotein–lipid interactions through a combination of elec-trostatic and hydrophobic mechanisms. Indeed,crystallographic studies with phosphoglyceride analogshave suggested that some of the bound Ca2+ ions may binddirectly to the oxygens of phospholipid head groups [35].In addition, Ca2+ binding to annexin V causes a buriedtryptophan residue (Try185) to become exposed on thesurface of the i-face [36,37] and the replacement of thistryptophan with an alanine residue has been shown todecrease the affinity of annexin V for model membranes[38]. Interestingly, studies of mutated forms of annexin Ihave provided evidence that individual domains of annex-ins, though structurally homologous, may have distinctfunctions in lipid-vesicle binding and aggregation [39]. Ifsimilar studies of other annexins support this possibility,structure/function studies involving mutations in thedomains that promote protein–lipid interactions mosteffectively might be very informative.
Vitamin-K-dependent plasma proteins bind to the extra-cellular surfaces of cells in response to injury andcontribute to the control of blood clotting reactions [40].They contain Gla (γ-carboxyglutamate) residues at their Ntermini that bind Ca2+ and promote the functional
attachment of the coagulation factors to lipid surfaces.Nelsestuen and Ostrowski suggest that these attachmentsmay depend on yet-to-be characterized, site-specificmechanisms involving one or more phosphoglyceride headgroups, rather than on nonspecific electrostatic orhydrophobic interactions.
The studies reviewed by Gelb, Cho and Wilton, and byNelsestuen and Ostrowski provide evidence that thei-faces of peripheral membrane proteins are heterogeneousand contain a great deal of detailed, structurally importantinformation. The full significance of this information maynot become clear until the corresponding membrane lipidinterfaces that contribute to protein–lipid interactions arebetter understood. The lipid bilayers of mammalian cellmembranes are also heterogeneous and structurally com-plex; however, most investigations of the lipids thatinteract with peripheral membrane proteins have beendone using relatively simple lipid systems that have a lim-ited potential for providing detailed structural information.Therefore, work with more informative lipid systems isneeded. The review by Brockman (pp 438–443) providesan indication of the type of information that will berequired. It shows how careful experimentation with lipidmonolayers can be used to obtain important insights aboutthe molecular role of lipids in protein–lipid interactions.
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Editorial overview Glomset 427
