ALS-associated mutation disturbs amyloid fibril formation of TIA-1 prion-like domain

Abstract

Abstract T-cell intracellular antigen-1 (TIA-1) is a key component of stress granules with an intrinsically disordered region called the prion-like domain (PLD). TIA-1 PLD forms phase-separated droplets that subsequently transition into amyloid fibrils. However, the structural basis of TIA-1 PLD amyloid fibril formation has not been elucidated. We investigated the amyloid fibril structure of TIA-1 PLD using cryo-electron microscopy and found structural features that ensure the reversibility of the fibrils, including a kinked backbone conformation, a polar zipper, and a proline-mediated cross-b structure. We also determined the amyloid fibril structure with the amyotrophic lateral sclerosis (ALS)-associated G355R mutation and found that G355R disrupts the tight conformation surrounding G355 in the wild-type fibril structure, resulting in destabilized and delayed amyloid fibril formation. The structural disturbance of amyloid fibril formation by G355R may contribute to the pathogenesis of ALS.