Human thrombopoietin structure-function relationships: identification of functionally important residues.
| References: | Nature. 1985 Feb 28-Mar 6;313(6005):806-10. (PMID: 3838366) J Biol Chem. 1997 Aug 15;272(33):20595-602. (PMID: 9252374) Mol Cell Biol. 1987 Aug;7(8):2745-52. (PMID: 3670292) EMBO J. 1988 Apr;7(4):1061-9. (PMID: 3261239) Br J Haematol. 1988 Jul;69(3):359-66. (PMID: 3261598) Science. 1989 Jun 2;244(4908):1081-5. (PMID: 2471267) Cell. 1990 Dec 21;63(6):1137-47. (PMID: 2175677) EMBO J. 1991 Dec;10(13):4105-12. (PMID: 1836758) Eur J Biochem. 1991 Dec 5;202(2):225-9. (PMID: 1761028) Science. 1992 Jan 17;255(5042):306-12. (PMID: 1549776) Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5640-4. (PMID: 1608974) EMBO J. 1993 Jul;12(7):2645-53. (PMID: 8334987) J Biol Chem. 1993 Jul 25;268(21):15983-93. (PMID: 8340419) Oncogene. 1993 Oct;8(10):2607-15. (PMID: 8397366) Nature. 1994 Jun 16;369(6481):533-8. (PMID: 8202154) Nature. 1994 Jun 16;369(6481):565-8. (PMID: 8202158) Nature. 1994 Jun 16;369(6481):568-71. (PMID: 8202159) Cell. 1994 Jul 1;77(7):1101-16. (PMID: 8020098) Cell. 1994 Jul 1;77(7):1117-24. (PMID: 8020099) J Biol Chem. 1994 Sep 9;269(36):22839-46. (PMID: 8077236) Blood. 1995 Jan 1;85(1):292-4. (PMID: 7803805) Stem Cells. 1994 Nov;12(6):586-98. (PMID: 7881359) Blood. 1995 Jul 1;86(1):54-9. (PMID: 7795256) Blood. 1995 Jul 15;86(2):419-31. (PMID: 7605981) Biochem Biophys Res Commun. 1995 Aug 24;213(3):1091-8. (PMID: 7654225) Ann N Y Acad Sci. 1995 Sep 7;766:253-62. (PMID: 7486668) Biochem Biophys Res Commun. 1995 Nov 2;216(1):338-47. (PMID: 7488109) Mol Pharmacol. 1995 Nov;48(5):783-9. (PMID: 7476907) Blood. 1996 Jun 15;87(12):4998-5005. (PMID: 8652812) Blood. 1996 Jun 15;87(12):5006-15. (PMID: 8652813) Science. 1996 Jul 26;273(5274):464-71. (PMID: 8662530) Blood. 1996 Sep 1;88(5):1619-31. (PMID: 8781417) Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9471-6. (PMID: 8790354) Protein Eng. 1995 Dec;8(12):1215-31. (PMID: 8869634) Biochemistry. 1996 Nov 26;35(47):14849-61. (PMID: 8942648) Blood. 1996 Dec 1;88(11):4124-31. (PMID: 8943846) EMBO J. 1996 Dec 2;15(23):6531-40. (PMID: 8978680) Biochem Biophys Res Commun. 1997 Feb 24;231(3):823-6. (PMID: 9070902) Leukemia. 1997 Apr;11(4):541-51. (PMID: 9096695) Nature. 1997 May 8;387(6629):206-9. (PMID: 9144295) Endocrinology. 1985 Jun;116(6):2286-92. (PMID: 3996312) |
|---|---|
| Substance Nomenclature: | 0 (Neoplasm Proteins) 0 (Proto-Oncogene Proteins) 0 (Receptors, Cytokine) 0 (Receptors, Thrombopoietin) 143641-95-6 (MPL protein, human) 9014-42-0 (Thrombopoietin) |
| Entry Date(s): | Date Created: 19980725 Date Completed: 19980923 Latest Revision: 20190501 |
| Update Code: | 20240829 |
| PubMed Central ID: | PMC1219638 |
| DOI: | 10.1042/bj3330729 |
| PMID: | 9677334 |
| Autor: | Jagerschmidt A; Synthélabo Recherche, Department of Genomic Biology, 10 rue des Carrières, 92500 Rueil-Malmaison, France., Fleury V, Anger-Leroy M, Thomas C, Agnel M, O'brien DP |
| Jazyk: | angličtina |
| Zdroj: | The Biochemical journal [Biochem J] 1998 Aug 01; Vol. 333 ( Pt 3), pp. 729-34. |
| DOI: | 10.1042/bj3330729 |
| Abstrakt: | Thrombopoietin (TPO) is a haematopoietic growth factor responsible for megakaryocyte progenitor proliferation and differentiation. It belongs to the four-helix-bundle cytokine family and exerts its biological effects through binding to a specific receptor, c-Mpl. With the use of site-directed mutagenesis we have generated 20 TPO mutants. Each of the TPO mutants was produced in a eukaryotic expression system and the mutants' ability to induce the proliferation of factor-dependent c-Mpl-expressing megakaryoblastic M-O7e cells was compared with that of wild-type TPO. Among the mutations studied, 10 lead to a significant decrease in TPO bioactivity. Of these ten residues, three are located in helix A of the protein (Arg10, Lys14 and Arg17) and four in helix D (His133, Gln132, Lys138 and Phe141), indicating that in TPO, as in other cytokines, these two helices are important for functional cytokine/receptor interactions. Surprisingly, mutant Arg10-->Ala (R10A) lacked any proliferative activity, despite the fact that this mutation was recently reported to have no effect on TPO/c-Mpl binding in a TPO phage ELISA [Pearce, Potts, Presta, Bald, Fendly and Wells (1997) J. Biol. Chem. 272, 20595-20602]. The lack of M-O7e proliferation is probably due to an inability of R10A mutant to promote receptor dimerization and thus receptor activation. Moreover we found that the Arg10 and Arg17 residues of TPO seem to be specific determinants for TPO/c-Mpl recognition. We also demonstrate that the O-glycosylation site located at position 110 of TPO is not necessary for the bioactivity of the cytokine. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|