A5066260202- Prion Diseases and Protein Misfolding
- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Amyotrophic Lateral Sclerosis Research
- Neurological diseases and metabolism
- HIV Research and Treatment
- S100 Proteins and Annexins
- Protein Degradation and Inhibitors
- Mitochondrial Function and Pathology
- Gender, Health, and Social Inequality
- RNA modifications and cancer
- Urticaria and Related Conditions
- Ubiquitin and proteasome pathways
- Muscle Physiology and Disorders
- Nuclear Receptors and Signaling
- Metabolism and Genetic Disorders
- RNA regulation and disease
- Genomics and Chromatin Dynamics
- Occupational Health and Safety in Workplaces
- Chemotherapy-related skin toxicity
- Prostate Cancer Treatment and Research
- Amino Acid Enzymes and Metabolism
- RNA and protein synthesis mechanisms
- Pediatric health and respiratory diseases
- Sex work and related issues
Universitat Autònoma de Barcelona
2015-2023
Institut de Recerca Sant Joan de Déu
2023
Hospital Sant Joan de Déu Barcelona
2023
Ventura College
2020
Instituto de Ciências Farmacêuticas
2001-2003
Transcription factors are among the most attractive therapeutic targets but considered largely 'undruggable' in part due to intrinsically disordered nature of their activation domains. Here we show that aromatic character domain androgen receptor, a target for castration-resistant prostate cancer, is key its activity as transcription factor, allowing it translocate nucleus and partition into transcriptional condensates upon by androgens. On basis our understanding interactions stabilizing...
Prion-like proteins form multivalent assemblies and phase separate into membraneless organelles. Heterogeneous ribonucleoprotein D-like (hnRNPDL) is a RNA-processing prion-like protein with three alternative splicing (AS) isoforms, which lack none, one, or both of its two disordered domains. It has been suggested that AS might regulate the assembly properties by controlling incorporation regions in isoforms. This, turn, would modulate their activity downstream program. Here, we demonstrate...
Amyloids consist of repetitions a specific polypeptide chain in regular cross-β-sheet conformation. Amyloid propensity is largely determined by the protein sequence, aggregation process being nucleated and short segments. Prions are special amyloids that become self-perpetuating after aggregation. responsible for neuropathology mammals, but they can also be functional, as yeast prions. The conversion these last proteins to prion state driven forming domains (PFDs), which generally large,...
Abstract Most pathogenic missense mutations cause specific molecular phenotypes through protein destabilization. However, how destabilization is manifested as a given phenotype not well understood. We develop here structural and energetic approach to describe mutational effects on traits such function, regulation, stability, subcellular targeting or aggregation propensity. This tested using large-scale experimental perturbation analyses in over thirty three different proteins...
Prion-like behaviour is attracting much attention due to the growing evidences that amyloid-like self-assembly may reach beyond neurodegeneration and be a conserved functional mechanism. The best characterized prions correspond subset of yeast proteins involved in translation or transcription. Their conformational promiscuity encoded Prion Forming Domains (PFDs), usually long intrinsically disordered protein segments low complexity. compositional bias these regions seems important for...
Around 1% of human proteins are predicted to contain a disordered and low complexity prion-like domain (PrLD). Mutations in PrLDs have been shown promote transition towards an aggregation-prone state several diseases. Recently, we that algorithm considers the effects mutations on composition, as well localized amyloid propensity can predict impact these amino acid changes protein intracellular aggregation. In this application note, implement concept into AMYCO web server, refined forecasts...
Amyloid fibrils formed by the islet amyloid polypeptide (IAPP) cause pancreatic beta-cell damage, resulting in reduced insulin secretion and Type 2 diabetes (T2D). Variations primary amino acid sequence of IAPP can influence its aggregation rate animals expressing variants that do not form amyloids, develop T2D. Conversely, specific single -acid changes are enough to accelerate rate. Understanding how mutations impact help gain mechanistic understanding into process pathogenic formation this...
Abstract A disordered to β-sheet transition was thought drive the functional switch of Q/N-rich prions, similar pathogenic amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) regions within yeast prion domains in amyloid formation. We show that many human prion-like (PrLDs) contain CC overlap with polyQ tracts. Most proteins bearing these are transcriptional coactivators, including Mediator complex subunit 15 (MED15) involved bridging enhancers and promoters....
Despite the significant efforts devoted to decipher particular protein features that encode for a prion or prion-like behavior, they are still poorly understood. The well-characterized yeast prions constitute an ideal model system address this question, because, in these proteins, activity can be univocally assigned specific region of their sequence, known as forming domain (PFD). These PFDs intrinsically disordered, relatively long and, many cases, low complexity, being enriched...
An increasing number of human proteins are being found to bear a prion-like domain (PrLD) driving the formation membraneless compartments through liquid-liquid phase separation. Point mutations in these PrLDs promote transition an amyloid-like state. There has been much debate on whether this aberrant aggregation is caused by compositional or sequential changes. A recent extensive mutational study ALS-associated hnRNPA2 protein provides framework discriminate molecular determinants behind...
Human prion-like proteins often correspond to nucleic acid binding proteins, displaying both globular domains and long intrinsically disordered regions (IDRs) (Harrison Shorter, 2017). Their IDRs are of low complexity resemble in amino composition the yeast prion domains, being usually enriched Gln Asn residues depleted hydrophobic charged residues. Accordingly, these sequence stretches named (PrLDs). Prion-like can aggregate into amyloid fibrils, which accommodate incoming protein monomers,...
Summary Transcription factors are among the most attractive therapeutic targets but considered largely undruggable due to intrinsically disordered nature of their activation domains. Here we show that aromatic character domain androgen receptor, a target for castration resistant prostate cancer, is key its activity as transcription factor by allowing it partition into transcriptional condensates. Based on this knowledge optimized structure small molecule inhibitor, previously identified...
Abstract Objective Mutations in ANXA11 cause amyotrophic lateral sclerosis (ALS) and have recently been identified as a of multisystem proteinopathy adult‐onset muscular dystrophy. These conditions are diseases result from the substitution Aspartate 40 (Asp40) for an apolar residue intrinsically disordered domain (IDD) ANXA11. Some ALS‐related variants known to affect IDD; however, mechanism by which myopathy occurs is unknown. Methods Genetic analysis was performed using WES‐trio. For study...