Structural basis for TIA-1 amyloid fibril formation revealed by cryo-EM

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.