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TitleStructural basis of MPL activation by thrombopoietin.
Journal, issue, pagesBlood Vessel Thromb Hemost, Vol. 1, Issue 3, Page 100018, Year 2024
Publish dateJul 16, 2024
AuthorsAmirhossein Mafi / Matthew Bratkowski / Jiefei Geng / Alyssa A Brito / Janani Sridar / Dongjian Hu / Anhdao T Darcy / Dhaval Nanavati / Nathan J Brown / Manoj K Rathinaswamy / Yuliya Kutskova / Dan Eaton / Qi Hao / Marcia Paddock
PubMed AbstractMyeloproliferative leukemia protein (MPL), also known as thrombopoietin (TPO) receptor, is a class I cytokine receptor that is expressed on hematopoietic progenitors, promoting growth and ...Myeloproliferative leukemia protein (MPL), also known as thrombopoietin (TPO) receptor, is a class I cytokine receptor that is expressed on hematopoietic progenitors, promoting growth and differentiation toward the megakaryocyte lineage and is critical for normal platelet production. Mutations in MPL, TPO, or Janus kinase 2 (JAK2) have been implicated in multiple diseases from congenital thrombocytopenias to myeloproliferative neoplasms. The ligand for MPL, TPO, stimulates platelet production by inducing MPL dimerization and results in an active conformation that allows downstream JAK2/STAT5 signaling. Despite the biological importance of this pathway, the molecular signaling mechanism remained unclear. Here, we present a 3.39-Å cryo-electron microscopy structure of the ectodomain of mouse MPL bound to TPO. The structure revealed both low and high affinity sites between MPL and TPO that contain several pathologic mutations. To better understand TPO-driven MPL signaling, we expanded upon this structure by molecular dynamic (MD) simulations to model the full-length human MPL/TPO complex, and showed that MPL D4-D4 domain interactions are functionally relevant in activity assays. To build on our understanding of downstream activation, we added JAK2 to the MPL/TPO complex by MD simulations. This ternary complex illustrates JAK2 dimerization through the pseudokinase domain, illustrates residues important for MPL interactions, and reveals the constitutive activation mechanism of patient mutant V617F. The model also suggests the mechanism of JAK2 tyrosine kinase domain transphosphorylation. Overall, our studies illuminate TPO/MPL/JAK2 signaling mechanisms and provide additional insight into the nature of receptor signaling, which will further benefit human health.
External linksBlood Vessel Thromb Hemost / PubMed:40766813 / PubMed Central
MethodsEM (single particle)
Resolution3.39 Å
Structure data

43526

8vu5

EMDB-43526, PDB-8vu5:
Cryo-EM structure of MPL bound to TPO
Method: EM (single particle) / Resolution: 3.39 Å

Source
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / Receptor / cytokine / complex / platelet synthesis

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