spectrin

Summary

Summary: A high molecular weight (220-250 kDa) water-soluble protein which can be extracted from erythrocyte ghosts in low ionic strength buffers. The protein contains no lipids or carbohydrates, is the predominant species of peripheral erythrocyte membrane proteins, and exists as a fibrous coating on the inner, cytoplasmic surface of the membrane.

Top Publications

  1. NANS A, Mohandas N, Stokes D. Native ultrastructure of the red cell cytoskeleton by cryo-electron tomography. Biophys J. 2011;101:2341-50 pubmed publisher
    Erythrocytes possess a spectrin-based cytoskeleton that provides elasticity and mechanical stability necessary to survive the shear forces within the microvasculature...
  2. Gushchina L, Gabdulkhakov A, Nikonov S, Filimonov V. High-resolution crystal structure of spectrin SH3 domain fused with a proline-rich peptide. J Biomol Struct Dyn. 2011;29:485-95 pubmed
    ..named WT-CIIA, was designed by connecting the proline-rich decapeptide PPPVPPYSAG to the C-terminus of the alpha-spectrin SH3 domain through a natural twelve-residue linker to obtain a single-chain model that would imitate ..
  3. Berger R, Hayes R, Richichi R, Beers S, Wang K. Serum concentrations of ubiquitin C-terminal hydrolase-L1 and ?II-spectrin breakdown product 145 kDa correlate with outcome after pediatric TBI. J Neurotrauma. 2012;29:162-7 pubmed publisher
    ..to measure serum concentrations of two novel serum biomarkers, ubiquitin C-terminal hydrolase (UCH-L1) and ?II-spectrin breakdown product 145 kDa (SBDP145), in children with TBI and healthy controls and to assess the ability of these ..
  4. Ruetz T, Cornick S, Guttman J. The spectrin cytoskeleton is crucial for adherent and invasive bacterial pathogenesis. PLoS ONE. 2011;6:e19940 pubmed publisher
    ..thorough studies detailing strategies microbes use to exploit these components of the host cell, the role of the spectrin-based cytoskeleton has been largely overlooked...
  5. Nestor M, Cai X, Stone M, Bloch R, Thompson S. The actin binding domain of ?I-spectrin regulates the morphological and functional dynamics of dendritic spines. PLoS ONE. 2011;6:e16197 pubmed publisher
    ..The ?I isoform of spectrin, a protein that links the actin cytoskeleton to membrane proteins, is present in spines...
  6. Abdi K, Bennett V. Adducin promotes micrometer-scale organization of beta2-spectrin in lateral membranes of bronchial epithelial cells. Mol Biol Cell. 2008;19:536-45 pubmed
    Adducin promotes assembly of spectrin-actin complexes, and is a target for regulation by calmodulin, protein kinase C, and rho kinase...
  7. Westphal D, Sytnyk V, Schachner M, Leshchyns ka I. Clustering of the neural cell adhesion molecule (NCAM) at the neuronal cell surface induces caspase-8- and -3-dependent changes of the spectrin meshwork required for NCAM-mediated neurite outgrowth. J Biol Chem. 2010;285:42046-57 pubmed publisher
    ..cell surface leads to activation of caspase-8 and -3 followed by the cleavage of the sub-membranous brain spectrin meshwork, but not of the actin or tubulin cytoskeleton...
  8. Zhang Z, Larner S, Liu M, Zheng W, Hayes R, Wang K. Multiple alphaII-spectrin breakdown products distinguish calpain and caspase dominated necrotic and apoptotic cell death pathways. Apoptosis. 2009;14:1289-98 pubmed publisher
    ..MTX-induced necrosis, as determined by the increased levels of calpain-specific cleaved fragments of spectrin by antibodies specific to the calpain-cleaved 150 kDa alphaII-spectrin breakdown product (SBDP150) and 145 kDa ..
  9. Mehboob S, Song Y, Witek M, Long F, Santarsiero B, Johnson M, et al. Crystal structure of the nonerythroid alpha-spectrin tetramerization site reveals differences between erythroid and nonerythroid spectrin tetramer formation. J Biol Chem. 2010;285:14572-84 pubmed publisher
    We have solved the crystal structure of a segment of nonerythroid alpha-spectrin (alphaII) consisting of the first 147 residues to a resolution of 2.3 A...

Scientific Experts

More Information

Publications62

  1. Massaro C, Pielage J, Davis G. Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton. J Cell Biol. 2009;187:101-17 pubmed publisher
    Loss of spectrin or ankyrin in the presynaptic motoneuron disrupts the synaptic microtubule cytoskeleton and leads to disassembly of the neuromuscular junction (NMJ)...
  2. Yamashita K, Suzuki A, Satoh Y, Ide M, Amano Y, Masuda Hirata M, et al. The 8th and 9th tandem spectrin-like repeats of utrophin cooperatively form a functional unit to interact with polarity-regulating kinase PAR-1b. Biochem Biophys Res Commun. 2010;391:812-7 pubmed publisher
    ..Utrophin is a large spectrin-like protein whose C-terminal domain mediates anchorage to a laminin receptor, dystroglycan (DG)...
  3. Gauthier E, El Nemer W, Wautier M, Renaud O, Tchernia G, Delaunay J, et al. Role of the interaction between Lu/BCAM and the spectrin-based membrane skeleton in the increased adhesion of hereditary spherocytosis red cells to laminin. Br J Haematol. 2010;148:456-65 pubmed publisher
    ..the unique erythroid receptor for laminin 511/521, interacts with the erythrocyte membrane skeleton through spectrin binding...
  4. Yamaguchi T, Ozaki S, Shimomura T, Terada S. Membrane perturbations of erythrocyte ghosts by spectrin release. J Biochem. 2007;141:747-54 pubmed
    The cytoskeleton plays an important role in the stability and function of the membrane. Spectrin release from erythrocyte ghosts makes the membrane more fragile. However, the detail of membrane fragility has remained unclear...
  5. Grubb M, Burrone J. Building and maintaining the axon initial segment. Curr Opin Neurobiol. 2010;20:481-8 pubmed publisher
  6. Thomas N, Shashikala S, Sengupta S. Cytoplasmic gamma-tubulin complex from brain contains nonerythroid spectrin. J Cell Biochem. 2010;110:1334-41 pubmed publisher
    ..brain cytoplasmic complex contains some high molecular weight proteins including alpha and beta nonerythroid spectrin which are not found in other tissues...
  7. Baines A. The spectrin-ankyrin-4.1-adducin membrane skeleton: adapting eukaryotic cells to the demands of animal life. Protoplasma. 2010;244:99-131 pubmed publisher
    ..These and other adaptations to animal life seem to require four proteins--spectrin, ankyrin, 4.1 and adducin--which emerged during eumetazoan evolution...
  8. Kolondra A, Lenoir M, Wolny M, Czogalla A, Overduin M, Sikorski A, et al. The role of hydrophobic interactions in ankyrin-spectrin complex formation. Biochim Biophys Acta. 2010;1798:2084-9 pubmed publisher
    b>Spectrin and ankyrin are the key components of the erythrocyte cytoskeleton...
  9. Pérez Munive C, Moreno Díaz de la Espina S. Nuclear spectrin-like proteins are structural actin-binding proteins in plants. Biol Cell. 2011;103:145-57 pubmed publisher
    ..ABPs in animals, such as lamins, lamin-associated proteins and nesprins, their genome does contain sequences with spectrin repeats and N-terminal calponin homology domains for actin binding that might be distant relatives of spectrin...
  10. Harper S, Sriswasdi S, Tang H, Gaetani M, Gallagher P, Speicher D. The common hereditary elliptocytosis-associated ?-spectrin L260P mutation perturbs erythrocyte membranes by stabilizing spectrin in the closed dimer conformation. Blood. 2013;122:3045-53 pubmed publisher
    ..hereditary pyropoikilocytosis (HPP) are common disorders of erythrocyte shape primarily because of mutations in spectrin. The most common HE/HPP mutations are located distant from the critical ??-spectrin tetramerization site, yet ..
  11. An X, Gauthier E, Zhang X, Guo X, Anstee D, Mohandas N, et al. Adhesive activity of Lu glycoproteins is regulated by interaction with spectrin. Blood. 2008;112:5212-8 pubmed publisher
    ..Lu and Lu(v13) are linked to the erythrocyte cytoskeleton through a direct interaction with spectrin. However, neither the molecular basis of the interaction nor its functional consequences have previously been ..
  12. Stabach P, Simonovic I, Ranieri M, Aboodi M, Steitz T, Simonovic M, et al. The structure of the ankyrin-binding site of beta-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties. Blood. 2009;113:5377-84 pubmed publisher
    b>Spectrin and ankyrin participate in membrane organization, stability, signal transduction, and protein targeting; their interaction is critical for erythrocyte stability...
  13. Winkels R, Jedlicka P, Weise F, Schultz C, Deller T, Schwarzacher S. Reduced excitability in the dentate gyrus network of betaIV-spectrin mutant mice in vivo. Hippocampus. 2009;19:677-86 pubmed publisher
    The submembrane cytoskeletal meshwork of the axon contains the scaffolding protein betaIV-spectrin. It provides mechanical support for the axon and anchors membrane proteins...
  14. Czogalla A, Jaszewski A, Diakowski W, Bok E, Jezierski A, Sikorski A. Structural insight into an ankyrin-sensitive lipid-binding site of erythroid beta-spectrin. Mol Membr Biol. 2007;24:215-24 pubmed
    It was recently shown that the region within beta-spectrin responsible for interactions with ankyrin includes a lipid-binding site which displayed sensitivity to inhibition by ankyrin...
  15. Kosaka T, Kosaka K. Heterogeneity of parvalbumin-containing neurons in the mouse main olfactory bulb, with special reference to short-axon cells and betaIV-spectrin positive dendritic segments. Neurosci Res. 2008;60:56-72 pubmed
    ..We examined the immuno-localization of the markers for the axon initial segments (AISs), betaIV-spectrin and sodium channels, to determine whether or not heterogeneous parvalbumin-positive neurons have axons...
  16. Susuki K, Rasband M. Molecular mechanisms of node of Ranvier formation. Curr Opin Cell Biol. 2008;20:616-23 pubmed publisher
    ..In the central nervous system, both glial soluble factors and paranodal axoglial junctions may function in a complementary manner to contribute to node formation. ..
  17. Blanc L, Salomao M, Guo X, An X, Gratzer W, Mohandas N. Control of erythrocyte membrane-skeletal cohesion by the spectrin-membrane linkage. Biochemistry. 2010;49:4516-23 pubmed publisher
    b>Spectrin tetramer is the major structural member of the membrane-associated skeletal network of red cells...
  18. Kolondra A, Grzybek M, Chorzalska A, Sikorski A. The 22.5 kDa spectrin-binding domain of ankyrinR binds spectrin with high affinity and changes the spectrin distribution in cells in vivo. Protein Expr Purif. 2008;60:157-64 pubmed publisher
    ..Therefore, cloned and bacterially expressed ankyrinR-spectrin-binding domain (AnkSBD) is a demanded tool for studying spectrin-ankyrin interactions...
  19. Harper S, Li D, Maksimova Y, Gallagher P, Speicher D. A fused alpha-beta "mini-spectrin" mimics the intact erythrocyte spectrin head-to-head tetramer. J Biol Chem. 2010;285:11003-12 pubmed publisher
    Head-to-head assembly of two spectrin heterodimers to form an actin-cross-linking tetramer is a physiologically dynamic interaction that contributes to red cell membrane integrity...
  20. Franke R, Scharnweber T, Fuhrmann R, Mrowietz C, Jung F. Effect of radiographic contrast media (Iodixanol, Iopromide) on the spectrin/actin-network of the membranous cytoskeleton of erythrocytes. Clin Hemorheol Microcirc. 2013;54:273-85 pubmed publisher
    ..The shape of the spectrin net was completely altered; from the more homogeneous distribution--typical of cells in autologous plasma and ..
  21. Chen T, Chen G, Funkhouser L, Nam S. Membrane domain modulation by Spectrins in Drosophila photoreceptor morphogenesis. Genesis. 2009;47:744-50 pubmed publisher
    Spectrins are major proteins in the cytoskeletal network of most cells. In Drosophila, beta(Heavy)-Spectrin encoded by the karst gene functions together with Crb during photoreceptor morphogenesis...
  22. Dong Z, Qi J, Peng H, Liu J, Zhang J. Spectrin domain of eukaryotic initiation factor 3a is the docking site for formation of the a:b:i:g subcomplex. J Biol Chem. 2013;288:27951-9 pubmed publisher
    ..this study, we used the tandem affinity purification approach in combination with tandem MS/MS and identified the spectrin domain of eIF3a as the docking site for the formation of eIF3(a:b:i:g) subcomplex...
  23. Li D, Tang H, Speicher D. A structural model of the erythrocyte spectrin heterodimer initiation site determined using homology modeling and chemical cross-linking. J Biol Chem. 2008;283:1553-62 pubmed
    b>Spectrin assembles into an anti-parallel heterodimeric flexible rod-like molecule through a multistep process initiated by a high affinity interaction between discrete complementary homologous motifs or "repeats" near the actin ..
  24. Dhermy D, Schrevel J, Lecomte M. Spectrin-based skeleton in red blood cells and malaria. Curr Opin Hematol. 2007;14:198-202 pubmed
    ..related to mutations of erythrocyte membrane proteins, molecular studies have shown the prevalence of particular spectrin mutations in patients from black ethnic extraction, leading one to question the selection of new malaria-..
  25. Thompson J, Ellis R, Green E, Winlove C, Petrov P. Spectrin maintains the lateral order in phosphatidylserine monolayers. Chem Phys Lipids. 2008;151:66-8 pubmed
    We investigate the effect of the skeletal protein spectrin on the lateral order in dipalmitoyl phosphatidylserine monolayers spread on aqueous surfaces using grazing incidence X-ray diffraction...
  26. Samanta S, Dutta D, Ghoshal A, Mukhopadhyay S, Saha B, Sundar S, et al. Glycosylation of erythrocyte spectrin and its modification in visceral leishmaniasis. PLoS ONE. 2011;6:e28169 pubmed publisher
    ..the identification of two high-molecular weight 9-O-acetylated sialoglycoproteins as human erythrocytic ?- and ?-spectrin. Total spectrin purified from erythrocytes of VL patients (spectrin(VL)) was reactive with Achatinin-H...
  27. Robledo R, Ciciotte S, Gwynn B, Sahr K, Gilligan D, Mohandas N, et al. Targeted deletion of alpha-adducin results in absent beta- and gamma-adducin, compensated hemolytic anemia, and lethal hydrocephalus in mice. Blood. 2008;112:4298-307 pubmed publisher
    In the red blood cell (RBC), adducin is present primarily as tetramers of alpha- and beta-subunits at spectrin-actin junctions, or junctional complexes. Mouse RBCs also contain small amounts of gamma-adducin...
  28. Wensley B, Batey S, Bone F, Chan Z, Tumelty N, Steward A, et al. Experimental evidence for a frustrated energy landscape in a three-helix-bundle protein family. Nature. 2010;463:685-8 pubmed publisher
    ..Such general observations cannot explain the folding behaviour of the R15, R16 and R17 domains of alpha-spectrin. R15 folds approximately 3,000 times faster than its homologues, although they have similar structures, ..
  29. Ipsaro J, Huang L, MONDRAGON A. Structures of the spectrin-ankyrin interaction binding domains. Blood. 2009;113:5385-93 pubmed publisher
    As key components of the erythrocyte membrane skeleton, spectrin and ankyrin specifically interact to tether the spectrin cytoskeleton to the cell membrane...
  30. Czogalla A, Sikorski A. Do we already know how spectrin attracts ankyrin?. Cell Mol Life Sci. 2010;67:2679-83 pubmed publisher
    The interaction of ankyrin and spectrin yields the major anchor between the membrane skeleton and the lipid bilayer...
  31. Baines A. Evolution of the spectrin-based membrane skeleton. Transfus Clin Biol. 2010;17:95-103 pubmed publisher
    A group of four proteins - spectrin, ankyrin, 4.1 and adducin - evolved with the metazoa...
  32. Lefferts J, Wang C, Sridharan D, Baralt M, Lambert M. The SH3 domain of alphaII spectrin is a target for the Fanconi anemia protein, FANCG. Biochemistry. 2009;48:254-63 pubmed publisher
    The structural protein nonerythroid alpha spectrin (alphaIISp) plays a role in the repair of DNA interstrand cross-links and is deficient in cells from patients with Fanconi anemia (FA), in which there is a defect in ability to repair ..
  33. Vaccaro M, Gigliotti S, Graziani F, Carotenuto R, De Angelis C, Tussellino M, et al. A transient asymmetric distribution of XNOA 36 mRNA and the associated spectrin network bisects Xenopus laevis stage I oocytes along the future A/V axis. Eur J Cell Biol. 2010;89:525-36 pubmed publisher
    ..This distribution is similar to that of alpha-spectrin mRNA...
  34. Susuki K, Raphael A, Ogawa Y, Stankewich M, Peles E, Talbot W, et al. Schwann cell spectrins modulate peripheral nerve myelination. Proc Natl Acad Sci U S A. 2011;108:8009-14 pubmed publisher
    ..Here, we demonstrate that the submembranous cytoskeletal proteins ?II and ?II spectrin are polarized in Schwann cells and colocalize with signaling molecules known to modulate myelination in vitro...
  35. Tjota M, Lee S, Wu J, Williams J, Khanna M, Thomas G. Annexin B9 binds to ?(H)-spectrin and is required for multivesicular body function in Drosophila. J Cell Sci. 2011;124:2914-26 pubmed publisher
    ..a relationship between the small Ca(2+)-dependent membrane-binding protein Annexin B9 (AnxB9), apical ?(Heavy)-spectrin (?(H)) and the multivesicular body (MVB) in Drosophila...
  36. Koshino I, Mohandas N, Takakuwa Y. Identification of a novel role for dematin in regulating red cell membrane function by modulating spectrin-actin interaction. J Biol Chem. 2012;287:35244-50 pubmed publisher
    ..constituent proteins of the membrane skeleton are phosphorylated by various kinases, and phosphorylation of ?-spectrin by casein kinase and of protein 4...
  37. Galiano M, Jha S, Ho T, Zhang C, Ogawa Y, Chang K, et al. A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Cell. 2012;149:1125-39 pubmed publisher
    ..break symmetry, they assemble a distal axonal submembranous cytoskeleton, comprised of ankyrinB (ankB), ?II-spectrin, and ?II-spectrin, that defines a boundary limiting ankG to the proximal axon...
  38. Krieger C, An X, Tang H, Mohandas N, Speicher D, Discher D. Cysteine shotgun-mass spectrometry (CS-MS) reveals dynamic sequence of protein structure changes within mutant and stressed cells. Proc Natl Acad Sci U S A. 2011;108:8269-74 pubmed publisher
    ..Cysteine shotgun labeling with fluorophores is analyzed here with mass spectrometry of the spectrin-actin membrane skeleton in sheared red blood cell ghosts from normal and diseased mice...
  39. Zhao K, Masci P, Lavin M. Disruption of spectrin-like cytoskeleton in differentiating keratinocytes by PKC? activation is associated with phosphorylated adducin. PLoS ONE. 2011;6:e28267 pubmed publisher
    b>Spectrin is a central component of the cytoskeletal protein network in a variety of erythroid and non-erythroid cells...
  40. Xu K, Zhong G, Zhuang X. Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science. 2013;339:452-6 pubmed publisher
    Actin and spectrin play important roles in neurons, but their organization in axons and dendrites remains unclear...
  41. Acsadi G, Moore S, Chéron A, Delalande O, Bennett L, Kupsky W, et al. Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy. J Biol Chem. 2012;287:18153-62 pubmed publisher
    ..Our results suggest that this missense mutation hinders the dynamic properties of the entire N-terminal region of dystrophin. ..
  42. Machnicka B, Grochowalska R, Bogusławska D, Sikorski A, Lecomte M. Spectrin-based skeleton as an actor in cell signaling. Cell Mol Life Sci. 2012;69:191-201 pubmed publisher
    ..We discuss new data concerning the commonly known role of the spectrin-based skeleton in control of membrane organization, stability and shape, and tethering protein mosaics to the ..
  43. Maeda O, Shibata K, Hosono S, Fujiwara S, Kajiyama H, Ino K, et al. Spectrin ?II and ?II tetramers contribute to platinum anticancer drug resistance in ovarian serous adenocarcinoma. Int J Cancer. 2012;130:113-21 pubmed publisher
    ..The purified proteins were identified as spectrin ?II and ?II by peptide mass mapping analysis...
  44. Ipsaro J, Huang L, Gutierrez L, Macdonald R. Molecular epitopes of the ankyrin-spectrin interaction. Biochemistry. 2008;47:7452-64 pubmed publisher
    Isoforms of ankyrin and its binding partner spectrin are responsible for a number of interactions in a variety of human cells...
  45. Gossai D, Lau Cam C. The effects of taurine, hypotaurine, and taurine homologs on erythrocyte morphology, membrane fluidity and cytoskeletal spectrin alterations due to diabetes, alcoholism and diabetes-alcoholism in the rat. Adv Exp Med Biol. 2009;643:369-79 pubmed publisher
    ..counteracting effects against alterations in erythrocyte (RBC) morphology, membrane fluidity and cytoskeletal spectrin distribution due to diabetes, alcoholism and diabetes-alcoholism in male Goto-Kakizaki rats (made diabetic with a ..
  46. Baines A. Evolution of spectrin function in cytoskeletal and membrane networks. Biochem Soc Trans. 2009;37:796-803 pubmed publisher
    b>Spectrin is a cytoskeletal protein thought to have descended from an alpha-actinin-like ancestor...
  47. Autore F, Pfuhl M, Quan X, Williams A, Roberts R, Shanahan C, et al. Large-scale modelling of the divergent spectrin repeats in nesprins: giant modular proteins. PLoS ONE. 2013;8:e63633 pubmed publisher
    Nesprin-1 and nesprin-2 are nuclear envelope (NE) proteins characterized by a common structure of an SR (spectrin repeat) rod domain and a C-terminal transmembrane KASH [Klarsicht-ANC-Syne-homology] domain and display N-terminal actin-..
  48. Brophy G, Pineda J, Papa L, Lewis S, Valadka A, Hannay H, et al. alphaII-Spectrin breakdown product cerebrospinal fluid exposure metrics suggest differences in cellular injury mechanisms after severe traumatic brain injury. J Neurotrauma. 2009;26:471-9 pubmed publisher
    Traumatic brain injury (TBI) produces alphaII-spectrin breakdown products (SBDPs) that are potential biomarkers for TBI...
  49. Kitisin K, Ganesan N, Tang Y, Jogunoori W, Volpe E, Kim S, et al. Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation. Oncogene. 2007;26:7103-10 pubmed
    ..Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs. ..
  50. Pinder J, Taylor Harris P, Bennett P, Carter E, Hayes N, King M, et al. Isoforms of protein 4.1 are differentially distributed in heart muscle cells: relation of 4.1R and 4.1G to components of the Ca2+ homeostasis system. Exp Cell Res. 2012;318:1467-79 pubmed publisher
    ..4.1G existed in an immunoprecipitable complex with spectrin and SERCA2. 80 kDa 4...
  51. Lee H, Zarnescu D, MacIver B, Thomas G. The cell adhesion molecule Roughest depends on beta(Heavy)-spectrin during eye morphogenesis in Drosophila. J Cell Sci. 2010;123:277-85 pubmed publisher
    ..Here we describe a novel relationship between the Crumbs partner beta(Heavy)-spectrin (beta(H)), the ZA and Roughest...
  52. Ipsaro J, MONDRAGON A. Structural basis for spectrin recognition by ankyrin. Blood. 2010;115:4093-101 pubmed publisher
    ..b>Spectrin, the principal component of this network, is anchored to membrane proteins through the adaptor protein ankyrin...
  53. Czogalla A, Grzymajło K, Jezierski A, Sikorski A. Phospholipid-induced structural changes to an erythroid beta spectrin ankyrin-dependent lipid-binding site. Biochim Biophys Acta. 2008;1778:2612-20 pubmed publisher
    The region of beta-spectrin that is responsible for interactions with ankyrin was shown to comprise an ankyrin-sensitive lipid-binding site...