Biology subjects

Fazekas, Z.

Publications and source records attributed to Fazekas, Z..

2 recordsLinked to original sources

bioRxiv2026

Hybrid Tetramers of Wild-Type and Amyloidogenic H88R Transthyretin Challenge the Monomer Paradigm

Hereditary transthyretin amyloidosis (ATTRv) is driven by mutations that destabilize the native tetrameric transthyretin (TTR), promoting monomer formation and amyloid aggregation. The H88R variant has been considered fully monomeric, yet its behavior in heterozygous patients has remained unclear. Here, we demonstrate that H88R TTR can form hybrid tetramers with wild-type chains, both in vitro and in patient sera. We considered all possible tetramers, along with various trimer and dimer constructions, and found that the stability of hybrid tetramers containing one or two mutant chains is not significantly reduced in comparison with of the wild-type tetramer, suggesting a practically unhindered entry for H88R TTR monomers into such hybrid tetrameric assemblies, facilitating their secretion. Mass spectrometry confirms incorporation of H88R chains into tetramers in vitro, and show that the H88R TTR variant is present in the serum of carriers albeit in low concentration. We propose that the scarcity of this variant is the result of its retention in the endoplasmic reticulum and present a model for the association of H88R TTR with the endoplasmic reticule chaperone Binding immunoglobulin Protein (BiP). These findings revise the current monomeric view of H88R TTR, with direct implications for the efficacy of tetramer-stabilizing therapeutics. Our results highlight a delicate balance between cellular retention and hybridization, informing mechanistic understanding and treatment strategies in heterozygous ATTRv patients.

molecular biology↗

bioRxiv2026

Evolutionarily Conserved Amyloid Aggregation in the PACAP Peptide Family Is Controlled by Heparin-Sensitive Lys/Arg Gatekeeper Residues

Functional amyloid formation plays a central role in the storage of several peptide hormones, yet its structural basis remains poorly understood. Here, we investigate amyloid formation within class B1 GPCR-associated peptide hormones by analysing the aggregation propensity of the PACAP family. We show that five of six human PACAP-family peptides form amyloid fibrils not only within the pH range characteristic of secretory granules; however, aggregation is strictly dependent on the presence of glycosaminoglycans such as heparin. We identify conserved Arg/Lys-rich regions as key regulatory elements that act as conditional switches within the PACAP family. Experimental and molecular dynamics simulations show these residues function as aggregation gatekeepers but promote peptide self-assembly upon charge compensation by polyanionic cofactors. Although the glucagon and PACAP families diverged early in chordate evolution, we demonstrate, supported by seven amyloid-like crystal structures, that receptor-binding segments of PACAP peptides also function as aggregation-prone regions despite substantial sequence divergence from their counterparts in the glucagon family. Profiling aggregation in protochordate-derived peptides approximating the ancestral state of the superfamily, combined with sequence analysis of vertebrate PACAP-glucagon peptides, reveals that the intrinsic aggregation profile is remarkably conserved throughout evolution, even as receptor specificity diversifies.

biochemistry↗