6NMY

A Cytokine-receptor complex

Summary for 6NMY

• Entry DOI: 10.2210/pdb6nmy/pdb
• Descriptor: Interleukin-3 receptor subunit alpha, Cytokine receptor common subunit beta, Interleukin-3, ... (9 entities in total)
• Functional Keywords: cytokine-receptor complex, receptor assembly, cell surface, cytokine
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 192064.24

Authors

Dhagat, U.,Kan, W.L.,Hercus, T.R.,Broughton, S.E.,Nero, T.L.,Lopez, A.F.,Parker, M.W. (deposition date: 2019-01-13, release date: 2020-01-22, Last modification date: 2024-10-16)

Primary citation

Kan, W.L.,Dhagat, U.,Kaufmann, K.B.,Hercus, T.R.,Nero, T.L.,Zeng, A.G.X.,Toubia, J.,Barry, E.F.,Broughton, S.E.,Gomez, G.A.,Benard, B.A.,Dottore, M.,Cheung Tung Shing, K.S.,Boutzen, H.,Samaraweera, S.E.,Simpson, K.J.,Jin, L.,Goodall, G.J.,Begley, C.G.,Thomas, D.,Ekert, P.G.,Tvorogov, D.,D'Andrea, R.J.,Dick, J.E.,Parker, M.W.,Lopez, A.F.
Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.
Cancer Discov, 13:1922-1947, 2023

PubMed Abstract: Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance.

PubMed: 37191437
DOI: 10.1158/2159-8290.CD-22-1396

Experimental method

X-RAY DIFFRACTION (3.301 Å)