ArticleThe Journal of biological chemistry2016
His499 Regulates Dimerization and Prevents Oncogenic Activation by Asparagine Mutations of the Human Thrombopoietin Receptor.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- The thrombopoietin receptor S264F mutant drives MPN with marrow fibrosis through a dual mechanism.HemaSphere · 2026Article
- Thrombopoietin Receptor MPL in Hematopoiesis and Myeloproliferative Neoplasms: Physiological Roles and Pathogenic Mechanisms.Stem cell reviews and reports · 2026Review
- Membrane-Based Assembly and Interactions in Immune Receptors.Chemical reviews · 2026Review
- MPL receptor dimerization and the thrombopoietin pathway in primary immune thrombocytopenia: from molecular mechanisms to targeted therapies.Frontiers in medicine · 2026Review
- Structural basis of MPL activation by thrombopoietin.Blood vessels, thrombosis & hemostasis · 2024Article
- Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin.Nature communications · 2024Article
- Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer.Journal of chemical information and modeling · 2023Article
- Constitutive Turbodomains enhance expansion and antitumor activity of allogeneic BCMA CAR T cells in preclinical models.Science advances · 2023Article
- ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis.Haematologica · 2023Article
- Article
- Structural modeling of cytokine-receptor-JAK2 signaling complexes using AlphaFold Multimer.bioRxiv : the preprint server for biology · 2023Article
- Spiers Memorial Lecture: Analysis andFaraday discussions · 2021Article
- In and out: Traffic and dynamics of thrombopoietin receptor.Journal of cellular and molecular medicine · 2021Review
- The thrombopoietin receptor: revisiting the master regulator of platelet production.Platelets · 2021Review
- Review
- Article
- Two activating mutations of MPL in triple-negative myeloproliferative neoplasms.Cancer medicine · 2019Article
- Article
- Article
- Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis.Frontiers in endocrinology · 2017Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
Ligand binding to the extracellular domain of the thrombopoietin receptor (TpoR) imparts a specific orientation on the transmembrane (TM) and intracellular domains of the receptors that is required for physiologic activation via receptor dimerization. To map the inactive and active dimeric orientations of the TM helices, we performed asparagine (Asn)-scanning mutagenesis of the TM domains of the murine and human TpoR. Substitution of Asn at only one position (S505N) activated the human receptor, whereas Asn substitutions at several positions activated the murine receptor. Second site mutational studies indicate that His(499) near the N terminus of the TM domain is responsible for protecting the human receptor from activation by Asn mutations. Structural studies reveal that the sequence preceding His(499) is helical in the murine receptor but non-helical in peptides corresponding to the TM domain of the inactive human receptor. The activating S505N mutation and the small molecule agonist eltrombopag both induce helix in this region of the TM domain and are associated with dimerization and activation of the human receptor. Thus, His(499) regulates the activation of human TpoR and provides additional protection against activating mutations, such as oncogenic Asn mutations in the TM domain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.