6RPY

Cytokine receptor-like factor 3 C-terminus residues 174-442: Hg-SAD derivative

Summary for 6RPY

• Entry DOI: 10.2210/pdb6rpy/pdb
• Related: 6RPX
• Descriptor: Cytokine receptor-like factor 3, MERCURY (II) ION (3 entities in total)
• Functional Keywords: platelet development, fibronectin domain, spry domain, blood clotting
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 1
• Total formula weight: 32263.84

Authors

Mifsud, R.W.,Yan, Y.,Bennett, C.,Read, R.J. (deposition date: 2019-05-15, release date: 2020-03-25, Last modification date: 2024-06-19)

Primary citation

Bennett, C.,Lawrence, M.,Guerrero, J.A.,Stritt, S.,Waller, A.K.,Yan, Y.,Mifsud, R.W.,Ballester-Beltran, J.,Baig, A.,Mueller, A.,Mayer, L.,Warland, J.,Penkett, C.J.,Akbari, P.,Moreau, T.,Evans, A.L.,Mookerjee, S.,Hoffman, G.J.,Saeb-Parsy, K.,Adams, D.J.,Couzens, A.L.,Bender, M.,Erber, W.N.,Nieswandt, B.,Read, R.J.,Ghevaert, C.
CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia.
Blood, 139:2227-2239, 2022

PubMed Abstract: The process of platelet production has so far been understood to be a 2-stage process: megakaryocyte maturation from hematopoietic stem cells followed by proplatelet formation, with each phase regulating the peripheral blood platelet count. Proplatelet formation releases into the bloodstream beads-on-a-string preplatelets, which undergo fission into mature platelets. For the first time, we show that preplatelet maturation is a third, tightly regulated, critical process akin to cytokinesis that regulates platelet count. We show that deficiency in cytokine receptor-like factor 3 (CRLF3) in mice leads to an isolated and sustained 25% to 48% reduction in the platelet count without any effect on other blood cell lineages. We show that Crlf3-/- preplatelets have increased microtubule stability, possibly because of increased microtubule glutamylation via the interaction of CRLF3 with key members of the Hippo pathway. Using a mouse model of JAK2 V617F essential thrombocythemia, we show that a lack of CRLF3 leads to long-term lineage-specific normalization of the platelet count. We thereby postulate that targeting CRLF3 has therapeutic potential for treatment of thrombocythemia.

PubMed: 35051265
DOI: 10.1182/blood.2021013113

Experimental method

X-RAY DIFFRACTION (1.97 Å)