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Phase Separation and Fibrillization of Human Annexin A7 Are Mediated by Its Proline-Rich Domain.

ABSTRACT: Human annexin A7, a calcium- and phospholipid-binding protein, governs calcium homeostasis, plasma membrane repair, apoptosis, and tumor progression. A7 contains an N-terminal proline-rich domain (PRD; 180 residues, ∼24% prolines) that determines its functional specificity. Using microscopy and dye-binding assays, we show that recombinant A7 and its isolated PRD spontaneously phase separate into spherical condensates, which subsequently transform into β-sheet-rich fibrils. We demonstrate that fibrillization of A7-PRD proceeds via primary nucleation and fibril-catalyzed secondary nucleation processes, as determined by chemical kinetics, providing a mechanistic basis for its amyloid assembly. This study confirms and highlights a subclass of eukaryotic PRDs prone to forming aggregates with important physiological and pathological implications.

SUBMITTER: Yu C

PROVIDER: S-EPMC10634317 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Phase Separation and Fibrillization of Human Annexin A7 Are Mediated by Its Proline-Rich Domain.

Yu Chenrong C Nelson Spencer L SL Meisl Georg G Ghirlando Rodolfo R Deshmukh Lalit L

Biochemistry 20231003 21

Human annexin A7, a calcium- and phospholipid-binding protein, governs calcium homeostasis, plasma membrane repair, apoptosis, and tumor progression. A7 contains an N-terminal proline-rich domain (PRD; 180 residues, ∼24% prolines) that determines its functional specificity. Using microscopy and dye-binding assays, we show that recombinant A7 and its isolated PRD spontaneously phase separate into spherical condensates, which subsequently transform into β-sheet-rich fibrils. We demonstrate that fi ...[more]

PMID: 37788367

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