Abstract
Chronic inflammation is involved in the provocation, progression, and exacerbation of various diseases, such as cancer and fibrosis. To treat these diseases, it is essential to understand their pathogenesis and develop therapeutic compounds that target the underlying signalling pathways. Recent technical advances in structural biology have enabled us to determine the high-resolution structures of important drug-target proteins, including membrane receptors and transporters, and thus structure-guided drug development has now become a realistic approach. In this chapter, we focus on two clinically important pathways involved in diseases associated with chronic inflammation, and summarise the recent results of our structural studies. In the first section, we focus on the signalling mediated by the lipid mediator lysophosphatidic acid, and discuss the structural findings for its producing enzyme and receptor. In the second section, we focus on the anaemia associated with inflammatory conditions, and discuss the structural insights into the iron exporter ferroportin, which plays a key role in the anaemia of chronic inflammation. These examples provide ideas for using structural information as the basis for pharmacological analyses.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906–19912. doi:10.1074/jbc.M000713200
Albers HMHG, Hendrickx LJD, van Tol RJP et al (2011) Structure-based design of novel boronic acid-based inhibitors of autotaxin. J Med Chem 54:4619–4626. doi:10.1021/jm200310q
Barbayianni E, Kaffe E, Aidinis V, Kokotos G (2015) Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer. Prog Lipid Res 58:76–96. doi:10.1016/j.plipres.2015.02.001
Bonaccorsi di Patti MC, Polticelli F, Cece G et al (2014) A structural model of human ferroportin and of its iron binding site. FEBS J 281:2851–2860. doi:10.1111/febs.12825
Bonaccorsi di Patti MC, Polticelli F, Tortosa V et al (2015) A bacterial homologue of the human iron exporter ferroportin. FEBS Lett 589:3829–3835. doi:10.1016/j.febslet.2015.11.025
Callebaut I, Joubrel R, Pissard S et al (2014) Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients. Hum Mol Genet 23:4479–4490. doi:10.1093/hmg/ddu160
Chrencik JE, Roth CB, Terakado M et al (2015) Crystal structure of antagonist bound human lysophosphatidic acid receptor 1. Cell 161:1633–1643. doi:10.1016/j.cell.2015.06.002
Donovan A, Brownlie A, Zhou Y et al (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781. doi:10.1038/35001596
Fernandes A, Preza GC, Phung Y et al (2009) The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood 114:437–443. doi:10.1182/blood-2008-03-146134
Fulkerson Z, Wu T, Sunkara M et al (2011) Binding of autotaxin to integrins localizes lysophosphatidic acid production to platelets and mammalian cells. J Biol Chem 286:34654–34663. doi:10.1074/jbc.M111.276725
Gräler M (2002) Lysophospholipids and their G protein-coupled receptors in inflammation and immunity. Biochim Biophys Acta - Mol Cell Biol Lipids 1582:168–174. doi:10.1016/S1388-1981(02)00152-X
Hanson MA, Roth CB, Jo E et al (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335:851–855. doi:10.1126/science.1215904
Hausmann J, Kamtekar S, Christodoulou E et al (2011) Structural basis of substrate discrimination and integrin binding by autotaxin. Nat Struct Mol Biol 18:198–204. doi:10.1038/nsmb.1980
Holbein BE (1981) Enhancement of Neisseria meningitidis infection in mice by addition of iron bound to transferrin. Infect Immun 34:120–125
Inoue A, Arima N, Ishiguro J et al (2011) LPA-producing enzyme PA-PLA1α regulates hair follicle development by modulating EGFR signalling. EMBO J 30:4248–4260. doi:10.1038/emboj.2011.296
Jordan JB, Poppe L, Haniu M et al (2009) Hepcidin revisited, disulfide connectivity, dynamics, and structure. J Biol Chem 284:24155–24167. doi:10.1074/jbc.M109.017764
Kawaguchi M, Okabe T, Okudaira S et al (2013) Screening and X-ray crystal structure-based optimization of autotaxin (ENPP2) inhibitors, using a newly developed fluorescence probe. ACS Chem Biol 8:1713–1721. doi:10.1021/cb400150c
Kihara Y, Maceyka M, Spiegel S, Chun J (2014) Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br J Pharmacol 171:3575–3594. doi:10.1111/bph.12678
Koyama M, Nishimasu H, Ishitani R, Nureki O (2012) Molecular dynamics simulation of Autotaxin: roles of the nuclease-like domain and the glycan modification. J Phys Chem B 116:11798–11808. doi:10.1021/jp303198u
Le Gac G, Ka C, Joubrel R et al (2013) Structure-function analysis of the human ferroportin iron exporter (SLC40A1): effect of hemochromatosis type 4 disease mutations and identification of critical residues. Hum Mutat 34:1371–1380. doi:10.1002/humu.22369
Mayr R, Griffiths WJH, Hermann M et al (2011) Identification of mutations in SLC40A1 that affect ferroportin function and phenotype of human ferroportin iron overload. Gastroenterology 140:2056–2063, 2063.e1. doi:10.1053/j.gastro.2011.02.064
McKie AT, Marciani P, Rolfs A et al (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309. doi:10.1016/S1097-2765(00)80425-6
Nakasaki T, Tanaka T, Okudaira S et al (2008) Involvement of the lysophosphatidic acid-generating enzyme autotaxin in lymphocyte-endothelial cell interactions. Am J Pathol 173:1566–1576. doi:10.2353/ajpath.2008.071153
Nemeth E, Rivera S, Gabayan V et al (2004a) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113:1271–1276. doi:10.1172/JCI200420945
Nemeth E, Tuttle MS, Powelson J et al (2004b) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093. doi:10.1126/science.1104742
Nishimasu H, Okudaira S, Hama K et al (2011) Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat Struct Mol Biol 18:205–212. doi:10.1038/nsmb.1998
Noguchi K, Herr D, Mutoh T, Chun J (2009) Lysophosphatidic acid (LPA) and its receptors. Curr Opin Pharmacol 9:15–23. doi:10.1016/j.coph.2008.11.010
Oikonomou N, Mouratis M-A, Tzouvelekis A et al (2012) Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol 47:566–574. doi:10.1165/rcmb.2012-0004OC
Parrill AL, Wang D, Bautista DL et al (2000) Identification of Edg1 receptor residues that recognize sphingosine 1-phosphate. J Biol Chem 275:39379–39384. doi:10.1074/jbc.M007680200
Preza GC, Ruchala P, Pinon R et al (2011) Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest 121:4880–4888. doi:10.1172/JCI57693
Pyne S, Kong K-C, Darroch PI (2004) Lysophosphatidic acid and sphingosine 1-phosphate biology: the role of lipid phosphate phosphatases. Semin Cell Dev Biol 15:491–501. doi:10.1016/j.semcdb.2004.05.007
Qiao B, Sugianto P, Fung E et al (2012) Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab 15:918–924. doi:10.1016/j.cmet.2012.03.018
Ross SL, Tran L, Winters A et al (2012) Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT. Cell Metab 15:905–917. doi:10.1016/j.cmet.2012.03.017
Schaible UE, Collins HL, Priem F, Kaufmann SHE (2002) Correction of the iron overload defect in −2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J Exp Med 196:1507–1513. doi:10.1084/jem.20020897
Sonoda H, Aoki J, Hiramatsu T et al (2002) A novel phosphatidic acid-selective phospholipase A1 that produces lysophosphatidic acid. J Biol Chem 277:34254–34263. doi:10.1074/jbc.M201659200
Stracke ML, Krutzsch HC, Unsworth EJ et al (1992) Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 267:2524–2529
Taniguchi R, Kato HE, Font J et al (2015) Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin. Nat Commun 6:8545. doi:10.1038/ncomms9545
Tokumura A, Majima E, Kariya Y et al (2002) Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 277:39436–39442. doi:10.1074/jbc.M205623200
Umezu-Goto M, Kishi Y, Taira A et al (2002) Autotaxin has lysophospholipase D activity leading to tumour cell growth and motility by lysophosphatidic acid production. J Cell Biol 158:227–233. doi:10.1083/jcb.200204026
van Meeteren LA, Moolenaar WH (2007) Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res 46:145–160. doi:10.1016/j.plipres.2007.02.001
Wallace DF, Harris JM, Subramaniam VN (2010) Functional analysis and theoretical modeling of ferroportin reveals clustering of mutations according to phenotype. Am J Physiol Cell Physiol 298:C75–C84. doi:10.1152/ajpcell.00621.2008
Wang DA, Lorincz Z, Bautista DL et al (2001) A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors. J Biol Chem 276:49213–49220. doi:10.1074/jbc.M107301200
Watanabe N, Ikeda H, Nakamura K et al (2007) Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C. J Clin Gastroenterol 41:616–623. doi:10.1097/01.mcg.0000225642.90898.0e
Yang F, Liu X-B, Quinones M et al (2002) Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J Biol Chem 277:39786–39791. doi:10.1074/jbc.M201485200
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Taniguchi, R., Nureki, O. (2016). Structural Biology of Chronic Inflammation-Associated Signalling Pathways: Toward Structure-Guided Drug Development. In: Miyasaka, M., Takatsu, K. (eds) Chronic Inflammation. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56068-5_6
Download citation
DOI: https://doi.org/10.1007/978-4-431-56068-5_6
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-56066-1
Online ISBN: 978-4-431-56068-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)