1v7n Citations

Structure of the receptor-binding domain of human thrombopoietin determined by complexation with a neutralizing antibody fragment.

Abstract

The cytokine thrombopoietin (TPO), the ligand for the hematopoietic receptor c-Mpl, acts as a primary regulator of megakaryocytopoiesis and platelet production. We have determined the crystal structure of the receptor-binding domain of human TPO (hTPO(163)) to a 2.5-A resolution by complexation with a neutralizing Fab fragment. The backbone structure of hTPO(163) has an antiparallel four-helix bundle fold. The neutralizing Fab mainly recognizes the C-D crossover loop containing the species invariant residue Q111. Titration calorimetric experiments show that hTPO(163) interacts with soluble c-Mpl containing the extracellular cytokine receptor homology domains with 1:2 stoichiometry with the binding constants of 3.3 x 10(9) M(-1) and 1.1 x 10(6) M(-1). The presence of the neutralizing Fab did not inhibit binding of hTPO(163) to soluble c-Mpl fragments, but the lower-affinity binding disappeared. Together with prior genetic data, these define the structure-function relationships in TPO and the activation scheme of c-Mpl.

Articles - 1v7n mentioned but not cited (8)

  1. Structure of the receptor-binding domain of human thrombopoietin determined by complexation with a neutralizing antibody fragment. Feese MD, Tamada T, Kato Y, Maeda Y, Hirose M, Matsukura Y, Shigematsu H, Muto T, Matsumoto A, Watarai H, Ogami K, Tahara T, Kato T, Miyazaki H, Kuroki R. Proc Natl Acad Sci U S A 101 1816-1821 (2004)
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Reviews citing this publication (18)

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Articles citing this publication (24)

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  2. Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ. Alvarado LJ, Huntsman HD, Cheng H, Townsley DM, Winkler T, Feng X, Dunbar CE, Young NS, Larochelle A. Blood 133 2043-2055 (2019)
  3. A rationally designed agonist antibody fragment that functionally mimics thrombopoietin. Frederickson S, Renshaw MW, Lin B, Smith LM, Calveley P, Springhorn JP, Johnson K, Wang Y, Su X, Shen Y, Bowdish KS. Proc Natl Acad Sci U S A 103 14307-14312 (2006)
  4. Grafting of thrombopoietin-mimetic peptides into cystine knot miniproteins yields high-affinity thrombopoietin antagonists and agonists. Krause S, Schmoldt HU, Wentzel A, Ballmaier M, Friedrich K, Kolmar H. FEBS J 274 86-95 (2007)
  5. Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim. Pecci A, Ragab I, Bozzi V, De Rocco D, Barozzi S, Giangregorio T, Ali H, Melazzini F, Sallam M, Alfano C, Pastore A, Balduini CL, Savoia A. EMBO Mol Med 10 63-75 (2018)
  6. Dissection of vertebrate hematopoiesis using zebrafish thrombopoietin. Svoboda O, Stachura DL, Machoňová O, Pajer P, Brynda J, Zon LI, Traver D, Bartůněk P. Blood 124 220-228 (2014)
  7. 'Crystal lattice engineering,' an approach to engineer protein crystal contacts by creating intermolecular symmetry: crystallization and structure determination of a mutant human RNase 1 with a hydrophobic interface of leucines. Yamada H, Tamada T, Kosaka M, Miyata K, Fujiki S, Tano M, Moriya M, Yamanishi M, Honjo E, Tada H, Ino T, Yamaguchi H, Futami J, Seno M, Nomoto T, Hirata T, Yoshimura M, Kuroki R. Protein Sci 16 1389-1397 (2007)
  8. Identification of the residues in the extracellular domain of thrombopoietin receptor involved in the binding of thrombopoietin and a nuclear distribution protein (human NUDC). Chen WM, Yu B, Zhang Q, Xu P. J Biol Chem 285 26697-26709 (2010)
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  10. Regulation of cell differentiation by hNUDC via a Mpl-dependent mechanism in NIH 3T3 cells. Zhang YP, Tang YS, Chen XS, Xu P. Exp Cell Res 313 3210-3221 (2007)
  11. The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis. Stockklausner C, Klotter AC, Dickemann N, Kuhlee IN, Duffert CM, Kerber C, Gehring NH, Kulozik AE. Blood 125 1159-1169 (2015)
  12. Identification and characterization of an alternative splice variant of Mpl with a high affinity for TPO and its activation of ERK1/2 signaling. Wang Q, Sun R, Wu L, Huang J, Wang P, Yuan H, Qiu F, Xu X, Wu D, Yu Y, Liu X, Zhang Q. Int J Biochem Cell Biol 45 2852-2863 (2013)
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  14. Eltrombopag: the discovery of a second generation thrombopoietin-receptor agonist. Stasi R. Expert Opin Drug Discov 4 85-93 (2009)
  15. Monoallelic loss-of-function THPO variants cause heritable thrombocytopenia. Cornish N, Aungraheeta MR, FitzGibbon L, Burley K, Alibhai D, Collins J, Greene D, Downes K, NIHR BioResource, Westbury SK, Turro E, Mumford AD. Blood Adv 4 920-924 (2020)
  16. Thrombopoietin-based CAR-T cells demonstrate in vitro and in vivo cytotoxicity to MPL positive acute myelogenous leukemia and hematopoietic stem cells. Zoine JT, Prince C, Story JY, Branella GM, Lytle AM, Fedanov A, Alexander JS, Porter CC, Doering CB, Spencer HT, Chandrakasan S. Gene Ther 29 1-12 (2022)
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  18. Determination of thrombopoietin-derived peptides recognized by both cellular and humoral immunities in healthy donors and patients with thrombocytopenia. Takedatsu H, Yoshimoto K, Okamura T, Miyazaki H, Kuwaki T, Sata M, Itoh K. Stem Cells 23 975-982 (2005)
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  21. Mutagenesis of the crystal contact of acidic fibroblast growth factor. Honjo E, Tamada T, Adachi M, Kuroki R, Meher A, Blaber M. J Synchrotron Radiat 15 285-287 (2008)
  22. Development of an Automated Chemiluminescent Enzyme Immunoassay for Measuring Thrombopoietin in Human Plasma. Nishikawa Y, Nishida S, Kuroda K, Kashiwagi H, Tomiyama Y, Kuwana M. Diagnostics (Basel) 12 313 (2022)
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Related citations provided by authors (1)

  1. Crystallization of the functional domain of human thrombopoietin using an antigen-binding fragment derived from neutralizing monoclonal antibody.. Kuroki R, Hirose M, Kato Y, Feese MD, Tamada T, Shigematsu H, Watarai H, Maeda Y, Tahara T, Kato T, Miyazaki H Acta Crystallogr D Biol Crystallogr 58 856-8 (2002)