8h0j
Annexin A5 mutant
Structural highlights
DiseaseANXA5_HUMAN Defects in ANXA5 are associated with susceptibility to pregnancy loss, recurrent, type 3 (RPRGL3) [MIM:614391. A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.[1] FunctionANXA5_HUMAN This protein is an anticoagulant protein that acts as an indirect inhibitor of the thromboplastin-specific complex, which is involved in the blood coagulation cascade. Publication Abstract from PubMedDespite the vital role of astrocytes in preserving blood-brain barrier (BBB) integrity, their therapeutic potential as targets in ischemic stroke-induced barrier disruption remains underexplored. We previously reported externalization of phosphatidylserine (PS) on astrocytic membranes concurrent with the emergence of PS externalization in neurons. PS externalization of astrocytes induced microglial phagocytosis of astrocytes, resulting in reduced astrocyte-vascular coupling and subsequent BBB breakdown. Annexin A5 (ANXA5) belongs to the superfamily of calcium (Ca(2+))- and phospholipid-binding proteins. Here, we report two X-ray structures of human ANXA5, including monomeric ANXA5 (1.42 A) and dimeric ANXA5 (1.80 A). Through the combination of molecular docking and functional analysis, we explored the mechanism of action of ANXA5 in stroke treatment. In addition, we observed a clear increase in therapeutic efficacy corresponding to the increased affinity of ANXA5 for PS. In summary, the phagocytosis of PS-externalized astrocytes by microglia has emerged as a critical mechanism driving BBB breakdown after ischemia. Our findings offer valuable structural insight into ANXA5 as an innovative pharmacological target for safeguarding blood-brain barrier integrity after cerebral ischemia. These insights may facilitate the development of novel PS-targeting medications aimed at achieving enhanced efficacy with minimal side effects. A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia.,Tang W, Cheng R, Gao MY, Hu MJ, Zhang L, Wang Q, Li XY, Yan W, Wang XY, Yang HM, Cheng J, Hua ZC Acta Pharmacol Sin. 2025 Apr;46(4):852-866. doi: 10.1038/s41401-024-01432-3. Epub , 2024 Dec 11. PMID:39663418[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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