7SFT

Filamin complex-2

7SFT の概要

• エントリーDOI: 10.2210/pdb7sft/pdb
• NMR情報: BMRB: 30958
• 分子名称: Filamin-A, Integrin alpha-IIb light chain, form 2 (2 entities in total)
• 機能のキーワード: filamin, integrin, inside-out signaling, outside-in signaling, cell adhesion, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 12344.51

構造登録者

Liu, J.,Qin, J. (登録日: 2021-10-04, 公開日: 2023-04-12, 最終更新日: 2024-05-15)

主引用文献

Liu, J.,Lu, F.,Ithychanda, S.S.,Apostol, M.,Das, M.,Deshpande, G.,Plow, E.F.,Qin, J.
A mechanism of platelet integrin alpha IIb beta 3 outside-in signaling through a novel integrin alpha IIb subunit-filamin-actin linkage.
Blood, 141:2629-2641, 2023

PubMed Abstract: The communication of talin-activated integrin αIIbβ3 with the cytoskeleton (integrin outside-in signaling) is essential for platelet aggregation, wound healing, and hemostasis. Filamin, a large actin crosslinker and integrin binding partner critical for cell spreading and migration, is implicated as a key regulator of integrin outside-in signaling. However, the current dogma is that filamin, which stabilizes inactive αIIbβ3, is displaced from αIIbβ3 by talin to promote the integrin activation (inside-out signaling), and how filamin further functions remains unresolved. Here, we show that while associating with the inactive αIIbβ3, filamin also associates with the talin-bound active αIIbβ3 to mediate platelet spreading. Fluorescence resonance energy transfer-based analysis reveals that while associating with both αIIb and β3 cytoplasmic tails (CTs) to maintain the inactive αIIbβ3, filamin is spatiotemporally rearranged to associate with αIIb CT alone on activated αIIbβ3. Consistently, confocal cell imaging indicates that integrin α CT-linked filamin gradually delocalizes from the β CT-linked focal adhesion marker-vinculin likely because of the separation of integrin α/β CTs occurring during integrin activation. High-resolution crystal and nuclear magnetic resonance structure determinations unravel that the activated integrin αIIb CT binds to filamin via a striking α-helix→β-strand transition with a strengthened affinity that is dependent on the integrin-activating membrane environment containing enriched phosphatidylinositol 4,5-bisphosphate. These data suggest a novel integrin αIIb CT-filamin-actin linkage that promotes integrin outside-in signaling. Consistently, disruption of such linkage impairs the activation state of αIIbβ3, phosphorylation of focal adhesion kinase/proto-oncogene tyrosine kinase Src, and cell migration. Together, our findings advance the fundamental understanding of integrin outside-in signaling with broad implications in blood physiology and pathology.

PubMed: 36867840
DOI: 10.1182/blood.2022018333

実験手法

SOLUTION NMR