Biology subjects

Duran-Romana, R.

Publications and source records attributed to Duran-Romana, R..

4 recordsLinked to original sources

bioRxiv2025

Energetic profiling reveals thermodynamic principles underlying amyloid fibril maturation

Amyloid fibrils adopt diverse structural polymorphs that underlie disease-specific phenotypes, but the thermodynamic principles guiding their formation and maturation remain poorly understood. Here, we apply energetic profiling to structural time series from cryo-EM datasets of IAPP, tau, and -synuclein to decode the principles governing fibril maturation, stability and polymorphic divergence. By mapping residue-level free energy contributions across experimentally resolved assembly pathways, we reconstruct the complex maturation trajectories of distinct amyloid systems. We find that amyloid assembly is driven by aggregation-prone regions that act as sequence-encoded stabilizing motifs. As assembly progresses, these motifs are reorganized and expanded, while additional regions introduce structural frustration that enables conformational flexibility. In several cases, environmental cofactors such as metal ions or polyanions are observed in association with regions of structural remodeling, where they may act to compensate for otherwise energetically strained conformations. Notably, structurally distinct polymorphs can exhibit similar energetic profiles, while polymorphs with similar folds may differ thermodynamically depending on their assembly environment. This framework connects polymorph structure to both encoded sequence features and extrinsic modifiers, offering mechanistic insight into how amyloid strains mature and diversify over time.

biophysics↗

bioRxiv2024

Analyzing the implications of protein folding delay caused by translation

Because of vectorial protein production, residues that interact in the native protein structure but are distantly separated in the primary sequence are unavailable simultaneously. Instead, there is a temporal delay during which the N-terminal interaction partner is vulnerable to off-pathway, non-native interactions. In this analysis, we introduce "FoldDelay" (FD), a metric that integrates the topological pattern of atomic interactions of the native structure with translation kinetics to quantify such time delays. The FD metric reveals that many proteins, particularly at eukaryotic translation rates, exhibit residues with FDs in the range of tens of seconds. These residues, predominantly in well-structured, buried regions, often coincide with predicted aggregation-prone regions. We show a correlation between FD and co-translational engagement by the yeast Hsp70 chaperone Ssb, suggesting that fold-delayed regions have a propensity to misfold. In support of this, we show that proteins with high FDs are more frequently co-translationally ubiquitinated and prone to aggregate upon Ssb deletion. Finally, we find that FD cannot be adequately reduced through codon optimization, highlighting the importance of co-translational chaperones to shield these vulnerable regions. This work offers insights into co-translational proteostasis and the delicate balance between efficient folding and potential misfolding and aggregation during translation.

molecular biology↗

bioRxiv2023

N-glycosylation as a eukaryotic protective mechanism against protein aggregation

The tendency for proteins to form aggregates is an inherent part of every proteome and arises from the self-assembly of short protein segments called aggregation-prone regions (APRs). While post-translational modifications (PTMs) have been implicated in modulating protein aggregation, their direct role in APRs remains poorly understood. In this study, we used a combination of proteome-wide computational analyses and biochemical techniques to investigate the potential involvement of PTMs in aggregation regulation. Our findings reveal that while most PTM types are disfavored near APRs, N-glycosylation is enriched and evolutionarily selected, especially in proteins prone to misfolding. Experimentally, we show that N-glycosylation inhibits the aggregation of peptides in vitro through steric hindrance. Moreover, mining existing proteomics data, we find that the loss of N-glycans at the flanks of APRs leads to specific protein aggregation in Neuro2a cells. Our results point towards a novel intrinsic role for N-glycosylation, directly preventing protein aggregation in eukaryotes.

molecular biology↗

bioRxiv2019

Identification of genomic enhancers through spatial integration of single-cell transcriptomics and epigenomics

Single-cell technologies allow measuring chromatin accessibility and gene expression in each cell, but jointly utilizing both layers to map bona fide gene regulatory networks and enhancers remains challenging. Here, we generate independent single-cell RNA-seq and single-cell ATAC-seq atlases of the Drosophila eye-antennal disc and spatially integrate the data using a virtual latent space that mimics the organization of the 2D tissue. To validate spatially predicted enhancers, we use a large collection of enhancer-reporter lines and identify [~]85% of enhancers in which chromatin accessibility and enhancer activity are coupled. Next, we infer enhancer-to-gene relationships in the virtual space, finding that genes are regulated by multiple redundant enhancers. Exploiting cell-type specific enhancers, we deconvolute cell-type specific effects of bulk-derived chromatin accessibility QTLs. Finally, we discover that Prospero drives neuronal differentiation through the binding of a GGG motif. In summary, we provide a comprehensive spatial characterization of gene regulation in a 2D tissue.

genomics↗