Structural basis for T-cell intracellular antigen-1 amyloid fibril formation revealed by cryo-electron microscopy

T-cell intracellular antigen-1 (TIA-1) is a key component of stress granules and contains an intrinsically disordered region called the prion-like domain (PLD). TIA-1 PLD can form condensates via phase separation that subsequently convert into amyloid fibrils. However, the structural basis underlying TIA-1 PLD amyloid fibril formation remains unclear, hindering clinical understanding and therapeutic intervention at the molecular level. Using cryo-electron microscopy, we identified structural features that are consistent with a labile architecture, including a kinked backbone conformation, a polar zipper, and a proline-mediated cross-β structure. We also determined the fibril structure containing a G355R missense mutation and found that this mutation disrupts the tight conformation around G355 in the wild-type structure, leading to delayed fibril formation. The amyloid fibril structures of TIA-1 PLD provide an atomic-level framework for mechanistic studies of mutation-driven dysfunction.

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Publication Details

Journal
PNAS Nexus
Published
2025-12-01
DOI
https://doi.org/10.1093/pnasnexus/pgaf388
Citations
1
Primary Topic
Prion Diseases and Protein Misfolding
Type
article
Field-Weighted Citation Impact
0.81

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Structural basis for T-cell intracellular antigen-1 amyloid fibril formation revealed by cryo-electron microscopy

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PNAS Nexus
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Structural basis for T-cell intracellular antigen-1 amyloid fibril formation revealed by cryo-electron microscopy

Naotaka Sekiyama, Yasuko Ohtani, E. Sakamoto, Tomoko Miyata, Norio Yoshida, Keiichi Namba, Takashi Kodama, Fumiaki Makino, Takayuki Kato, Daigo Inaoka, Kayo Imamura, Hidehito Tochio, Ryoga Kobayashi, Miu Ekari
article en
1 citations

Abstract

T-cell intracellular antigen-1 (TIA-1) is a key component of stress granules and contains an intrinsically disordered region called the prion-like domain (PLD). TIA-1 PLD can form condensates via phase separation that subsequently convert into amyloid fibrils. However, the structural basis underlying TIA-1 PLD amyloid fibril formation remains unclear, hindering clinical understanding and therapeutic intervention at the molecular level. Using cryo-electron microscopy, we identified structural features that are consistent with a labile architecture, including a kinked backbone conformation, a polar zipper, and a proline-mediated cross-β structure. We also determined the fibril structure containing a G355R missense mutation and found that this mutation disrupts the tight conformation around G355 in the wild-type structure, leading to delayed fibril formation. The amyloid fibril structures of TIA-1 PLD provide an atomic-level framework for mechanistic studies of mutation-driven dysfunction.

PNAS NexusVol. 4(12)
JEOL (Japan) (JP), Kyoto University (JP), Ube Frontier University (JP), Protein Research Foundation (JP), Nagoya University (JP), Futaba (Japan) (JP), The University of Osaka (JP)
Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Japan Society for the Promotion of Science
Openalex Percentile: Top 21%
Prion Diseases and Protein Misfolding
0.81
DOIOpen Access PDFOpenAlex
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