Biology subjects

Tagad, H.

Publications and source records attributed to Tagad, H..

3 recordsLinked to original sources

bioRxiv2026

An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism

ATTR amyloidosis is caused by transthyretin (TTR) amyloid deposition, yet the sequence-encoded events linking TTR misfolding to fibril nucleation and structural polymorphism remain incompletely defined. Here, we exploit the modular organization of patient-derived TTR fibrils to investigate two components of the pathological core: an N-terminal beta-hairpin spanning residues 11-35 (N-TTR) and a larger C-terminal fragment spanning residues 57-123 (C-TTR). Both fragments independently form beta-rich amyloid fibrils, as demonstrated by electron microscopy, circular dichroism, and fluorescence spectroscopy. Yet, their activities differ markedly. N-TTR fibrils promote full-length TTR aggregation and seed in an engineered cellular biosensor platform established to detect templated TTR assembly, whereas C-TTR aggregates show no detectable templating activity. Cryo-electron microscopy reveals two N-TTR polymorphs that preserve structural features of disease-derived folds, while energetic profiling identifies N-TTR as a stabilizing hotspot within ex vivo structures, providing a basis for this templating functionality. These findings reveal a functional hierarchy among amyloidogenic segments of TTR, since distinct regions form fibrils independently, but only those with structural compatibility efficiently template the parent protein. N-TTR therefore represents an autonomous amyloidogenic segment that links local sequence propensity to TTR nucleation, templating, and fibril polymorphism.

biophysics↗

bioRxiv2026

A functional amyloid scaffold shapes insect egg coats

Functional amyloids serve as structural scaffolds across biology, yet the molecular architecture and assembly principles of many remain unresolved. The lepidopteran egg coat, or chorion, presents a striking example: hundreds of paralogous proteins sharing a conserved central domain form a mechanically resilient amyloid matrix essential for embryo protection. Here, combining evolutionary analysis of more than 500 sequences with cryo-electron microscopy and biophysical assays, we determine the atomic structure of chorion amyloid filaments and uncover the principles governing their assembly. Contrary to previous structural predictions, chorion filaments adopt a {beta}-serpentine fold stabilized by a short hexapeptide motif that forms homotypic steric-zipper interfaces, self-assembles autonomously, and seeds full-length filament growth. Amyloid formation proceeds through secondary nucleation, while thermodynamic and structural analyses support a hierarchical assembly mechanism in which motif-driven interactions nucleate filament formation prior to consolidation of the mature yet lalbile protofilament core. These findings establish the molecular basis of insect egg-coat assembly and demonstrate that mechanisms commonly associated with pathological aggregation can also operate within a biologically regulated functional amyloid framework.

biophysics↗

bioRxiv2025

TAF15 amyloids propagate via defined motifs in a prion-like fashion

TATA-box binding protein-associated factor 15 (TAF15) is an RNA-binding member of the FET family recently identified as the primary fibrillar constituent in a subset of frontotemporal lobar degeneration (FTLD-FET) cases. Although TAF15 is also linked to amyotrophic lateral sclerosis (ALS), the molecular basis and propagation behavior of its aggregates remain unknown. In this work, we show that recombinant TAF15 forms amyloid fibrils under physiological conditions and developed a single-fluorophore TAF15 biosensor to quantitatively monitor their cellular propagation. Using this system, we demonstrate that both recombinant TAF15 fibrils and pathological aggregates extracted from atypical FTLD with ubiquitin inclusions (aFTLD-U) patient brains seed aggregation efficiently and transmit serially between cells, demonstrating hallmark features of prion-like propagation. Seeding was specific to TAF15 and absent for other amyloidogenic proteins, including the homologous protein fused-in-sarcoma (FUS), revealing an unexpected cross-seeding barrier. Occasional colocalization of FUS within TAF15 inclusions was observed upon transient co-expression, suggesting that FUS can be passively recruited rather than acting as an inducer of pathology in FTLD-FET brains. Computational and peptide-based experimental mapping identified multiple aggregation-prone regions within the TAF15 low-complexity domain that coincide with hotspots stabilizing the core of ex vivo TAF15 amyloid fibrils. These short motifs encode the propagation propensity of TAF15 aggregation in vitro and in cells. Together, these findings establish TAF15 as a bona fide amyloid-forming, prion-like protein and define the sequence grammar underlying its self-assembly, providing a mechanistic framework for its role in FTLD-FET and ALS and offering tractable molecular targets for therapeutic intervention.

biophysics↗