Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3.

ABSTRACT: hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids. The high-resolution amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The RNA binding domains are located as a solenoidal coat around the core. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMD D3 might be a loss-of-function disease as

SUBMITTER: Garcia-Pardo J 

PROVIDER: S-EPMC9842712 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature