Cryo-EM structures of functional and pathological amyloid ribonucleoprotein assemblies

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Amyloids play critical roles in biological systems but are also linked to neurodegenerative and systemic diseases.
• Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins (RBPs) involved in RNA biogenesis, with some containing disease-associated prion-like sequences.
• hnRNPs can form functional amyloid fibrils, but mutations can lead to pathological conditions.

Purpose of the Study:

• To provide a comprehensive overview of the structures of amyloid assemblies formed by hnRNPs and related RBPs.
• To explore the functional and pathological implications of these diverse amyloid structures.
• To highlight recent advances in cryo-electron microscopy (cryo-EM) for studying these assemblies.

Main Methods:

• Review of recent scientific literature focusing on amyloid structures.
• Analysis of cryo-electron microscopy (cryo-EM) data for hnRNPs and related RBPs.
• Integration of structural findings with functional and pathological data.

Main Results:

• Cryo-EM has yielded high-resolution structures of various amyloid assemblies formed by hnRNPs (e.g., hnRNPA1, hnRNPA2, hnRNPDL-2) and related proteins (e.g., TDP-43, FUS, Orb2).
• These structures reveal diverse fibril architectures, providing molecular insights into their formation and function.
• The findings link specific structural features to both normal cellular roles and disease pathogenesis.

Conclusions:

• Structural insights into hnRNP-containing amyloids are crucial for understanding their dual roles in health and disease.
• Advances in cryo-EM are revolutionizing the study of these complex biomolecular assemblies.
• Further research into these structures may lead to therapeutic strategies for amyloid-related diseases.