Biology subjects

Beales, C. T.

Publications and source records attributed to Beales, C. T..

3 recordsLinked to original sources

bioRxiv2026

Interdigitating coiled-coil tetramers define the helical architecture of GFAP filaments in astrocytes

GFAP filaments are core elements of the cytoskeleton in astrocytes, shaping cellular processes and influencing central nervous system function and pathology. How these filaments are built at the molecular level has remained unclear. Using cryo-electron microscopy and cryo-electron tomography, we show that GFAP filaments are helical polymers assembled from extended and twisted coiled-coil tetramers that interdigitate to form a complex filament tube. In the filament lumen, the low-complexity head domains aggregate to form a flexible fibre, while the tail domains extend from the surface and facilitate higher-order bundling of the filaments, indicating that both the low-complexity structural regions and the well-ordered coiled-coils of the filament tube contribute to the unique structure of GFAP filaments. Our findings provide molecular insights into the pathogenesis of Alexander Disease, localising multiple deleterious mutations to the critical interlock interaction between successive tetramers emergent in the final filament assembly.

neuroscience↗

bioRxiv2023

Vimentin filaments integrate low complexity domains in a highly complex helical structure

Intermediate filaments (IFs) are integral components of the cytoskeleton. They provide cells with tissue-specific mechanical properties and are involved in numerous cellular processes. Due to their intricate architecture, a 3D structure of IFs has remained elusive. Here we use cryo-focused ion beam milling, cryo-electron microscopy and tomography, to obtain a 3D structure of vimentin IFs (VIFs). VIFs assemble into a modular, densely-packed and highly-ordered helical symmetric structure of 40 -helices in cross-section, organized into 5 protofibrils. Surprisingly, the intrinsically disordered head domains form an amyloid-like fiber in the center of VIFs, while the intrinsically disordered tails form lateral connections between the protofibrils. Our findings demonstrate how protein domains of low sequence complexity can complement well-folded protein domains to construct a biopolymer with striking strength and stretchability.

biochemistry↗

bioRxiv2020

Sister-chromatid-sensitive Hi-C reveals the conformation of replicated human chromosomes

The three-dimensional organization of the genome supports regulated gene expression, recombination, DNA repair, and chromosome segregation during mitosis. Chromosome conformation capture (Hi-C)1-3 has revealed a complex genomic landscape of internal chromosome structures in vertebrate cells4-11 yet how sister chromatids topologically interact in replicated chromosomes has remained elusive due to their identical sequences. Here, we present sister-chromatid-sensitive Hi-C (scsHi-C) based on nascent DNA labeling with 4-thio-thymidine. Genome-wide conformation maps of human chromosomes revealed that sister chromatid pairs interact most frequently at the boundaries of topologically associating domains (TADs). Continuous loading of a dynamic cohesin pool separates sister-chromatid pairs inside TADs and is required to focus sister chromatid contacts at TAD boundaries. We identified a subset of TADs that are overall highly paired, characterized by facultative heterochromatin, as well as insulated topological domains that form separately within individual sister chromatids. The rich pattern of sister chromatid topologies and our scsHi-C technology will make it possible to dissect how physical interactions between identical DNA molecules contribute to DNA repair, gene expression, chromosome segregation, and potentially other biological processes.

cell biology↗