Journal Article

Molecular structure and interactions within amyloid-like fibrils formed by a low-complexity protein sequence from FUS

Lee, Myungwoon, Kato, Masato, Thurber, Kent R., Ghosh, Ujjayini, Tycko, Robert

2020

Overview

Protein domains without the usual distribution of amino acids, called low complexity (LC) domains, can be prone to self-assembly into amyloid-like fibrils. Self-assembly of LC domains that are nearly devoid of hydrophobic residues, such as the 214-residue LC domain of the RNA-binding protein FUS, is particularly intriguing from the biophysical perspective and is biomedically relevant due to its occurrence within neurons in amyotrophic lateral sclerosis, frontotemporal dementia, and other neurodegenerative diseases. We report a high-resolution molecular structural model for fibrils formed by the C-terminal half of the FUS LC domain (FUS-LC-C, residues 111-214), based on a density map with 2.62 Å resolution from cryo-electron microscopy (cryo-EM). In the FUS-LC-C fibril core, residues 112-150 adopt U-shaped conformations and form two subunits with in-register, parallel cross-β structures, arranged with quasi-2 1 symmetry. All-atom molecular dynamics simulations indicate that the FUS-LC-C fibril core is stabilized by a plethora of hydrogen bonds involving sidechains of Gln, Asn, Ser, and Tyr residues, both along and transverse to the fibril growth direction, including diverse sidechain-to-backbone, sidechain-to-sidechain, and sidechain-to-water interactions. Nuclear magnetic resonance measurements additionally show that portions of disordered residues 151-214 remain highly dynamic in FUS-LC-C fibrils and that fibrils formed by the N-terminal half of the FUS LC domain (FUS-LC-N, residues 2-108) have the same core structure as fibrils formed by the full-length LC domain. These results contribute to our understanding of the molecular structural basis for amyloid formation by FUS and by LC domains in general. The low-complexity (LC) domain mediates liquid-liquid phase separation and fibril formation of the RNA-binding protein FUS (FUsed in Sarcoma). Here, the authors combine cryo-EM, solid-state NMR measurements and MD simulations to structurally characterise the fibrils formed by the C-terminal half of the FUS LC domain and discuss stabilizing interactions within the fibril core.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/6 / 140/131 / 147/28 / 631/45/535/878 / 631/535/1258/1259 / 631/57/2272/2276 / 82/80 / Amino acid sequence / Amino acids / Amyloid - chemistry / Amyloid - genetics / Amyloid - metabolism / Amyloid - ultrastructure / Amyotrophic lateral sclerosis / Complexity / Cryoelectron Microscopy / Dementia disorders / Electron microscopy / Fibrillogenesis / Frontotemporal dementia / FUS protein / Humanities and Social Sciences / Humans / Hydrogen Bonding / Hydrogen bonds / Hydrophobicity / Liquid phases / Magnetic Resonance Spectroscopy / Molecular dynamics / Molecular Dynamics Simulation / Molecular Structure / multidisciplinary / Neurodegenerative diseases / NMR / Nuclear magnetic resonance / Phase separation / Protein Conformation / Protein Domains / Protein Interaction Domains and Motifs / Proteins / Residues / Ribonucleic acid / RNA / RNA-binding protein / RNA-Binding Protein FUS - chemistry / RNA-Binding Protein FUS - genetics / RNA-Binding Protein FUS - metabolism / RNA-Binding Protein FUS - ultrastructure / Sarcoma / Science / Science (multidisciplinary) / Self-assembly / Sequence Analysis, Protein / Structural models