Functional characterization of c-Mpl ectodomain mutations that underlie congenital amegakaryocytic thrombocytopenia
- Author(s)
- Varghese, LN; Zhang, JG; Young, SN; Willson, TA; Alexander, WS; Nicola, NA; Babon, JJ; Murphy, JM;
- Details
- Publication Year 2014-01-20,Volume 32,Issue #1,Page 18-26
- Journal Title
- Growth Factors
- Publication Type
- Journal Article
- Abstract
- Abstract Activation of the cell surface receptor, c-Mpl, by the cytokine, thrombopoietin (TPO), underpins megakaryocyte and platelet production in mammals. In humans, mutations in c-Mpl have been identified as the molecular basis of Congenital Amegakaryocytic Thrombocytopenia (CAMT). Here, we show that CAMT-associated mutations in c-Mpl principally lead to defective receptor presentation on the cell surface. In contrast, one CAMT mutant c-Mpl, F104S, was expressed on the cell surface, but showed defective TPO binding and receptor activation. Using mutational analyses, we examined which residues adjacent to F104 within the membrane-distal cytokine receptor homology module (CRM) of c-Mpl comprise the TPO-binding epitope, revealing residues within the predicted Domain 1 E-F and A-B loops and Domain 2 F'-G' loop as key TPO-binding determinants. These studies underscore the importance of the c-Mpl membrane-distal CRM to TPO-binding and suggest that mutations within this CRM that perturb TPO binding could give rise to CAMT.
- Publisher
- Informa
- Keywords
- Congenital amegakaryocytic thrombocytopenia, ligand binding, Mpl, TPO47
- Research Division(s)
- Cancer And Haematology; Molecular Medicine; Structural Biology
- Publisher's Version
- https://doi.org/10.3109/08977194.2013.874347
- NHMRC Grants
- NHMRC/1016647,
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- Copyright © 2014 Informa Plc. All rights reserved.
Creation Date: 2014-01-24 12:02:24