8H9Z

Annexin A5 protein mutant

Summary for 8H9Z

• Entry DOI: 10.2210/pdb8h9z/pdb
• Descriptor: Annexin A5, CALCIUM ION (3 entities in total)
• Functional Keywords: calcium-binding, apoptosis-detection, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36330.33

Authors

Hua, Z.C.,Tang, W. (deposition date: 2022-10-26, release date: 2023-11-01, Last modification date: 2025-05-28)

Primary citation

Tang, W.,Cheng, R.,Gao, M.Y.,Hu, M.J.,Zhang, L.,Wang, Q.,Li, X.Y.,Yan, W.,Wang, X.Y.,Yang, H.M.,Cheng, J.,Hua, Z.C.
A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia.
Acta Pharmacol.Sin., 46:852-866, 2025

PubMed Abstract: Despite 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)- and phospholipid-binding proteins. Here, we report two X-ray structures of human ANXA5, including monomeric ANXA5 (1.42 Å) and dimeric ANXA5 (1.80 Å). 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.

PubMed: 39663418
DOI: 10.1038/s41401-024-01432-3

Experimental method

X-RAY DIFFRACTION (1.42 Å)