Biology subjects

Velasco-Estevez, M.

Publications and source records attributed to Velasco-Estevez, M..

6 recordsLinked to original sources

bioRxiv2026

PepSpace: An Automated, Physics-Driven Directed Evolution Platform for the De Novo Design of Specific Peptide Binders and Condensate Modulators

Intrinsically disordered proteins, topologically complex protein surfaces, and biomolecular condensates regulate essential cellular processes but remain difficult to drug with conventional small molecules. Here, we present PepSpace, a physics-driven directed-evolution platform coupling residue-resolution coarse-grained molecular dynamics with a multi-objective genetic algorithm. PepSpace designs peptide binders by rewarding target engagement while penalizing peptide self-association and off-target binding. Evaluated alongside deep-learning generative models across multiple targets, PepSpace-designed peptides achieve predicted interaction strengths up to two orders of magnitude greater than machine-learning designs, while reproducing experimentally observed binding hierarchies and revealing distinct binding modes. For PIEZO1, PepSpace designs 25-mer peptides that preferentially engage a defined 30-residue intracellular beam epitope while suppressing interactions with the remainder 2,547-residues of the protein. For CHERP biomolecular condensates, dual-action peptides weaken native intermolecular contacts and destabilize the condensed phase. PepSpace provides a physically grounded framework for de novo peptide design against dynamic protein targets and biomolecular condensates, with explicit control over specificity, solubility, and collective interactions.

biophysics↗

bioRxiv2026

Size Control of hnRNPK-based Nucleolar Condensates by RNA-Regulated Fusion Dynamics

Nucleoli are liquid-like condensates whose size is actively conserved--they remain small, numerous, and resistant to coalescence--yet the molecular mechanisms that constrain their fusion remain poorly understood. Heterogeneous nuclear ribonucleoprotein K (hnRNPK), an RNA-binding protein implicated in nucleolar organization and cancer, interacts directly with the scaffold protein Nucleolin. Combining residue-resolution coarse-grained simulations with biochemical experiments, we find that hnRNPK and Nucleolin condense through distinct interaction networks--a localized cation-{pi}/electrostatic hotspot in hnRNPK versus broadly distributed electrostatic contacts in Nucleolin, reorganized upon co-assembly. To probe how RNAs reshape these condensates, we develop and validate, against re-entrant phase-separation experiments and AlphaLISA binding data, a nucleotide-resolution coarse-grained model for single-stranded RNA. Using this framework, we show that RNA is asymmetrically and preferentially recruited by hnRNPK over Nucleolin, an asymmetry that grows stronger when the two proteins compete for the same RNAs. This selective recruitment sustains a dynamic fission-fusion equilibrium: hnRNPK-containing condensates repeatedly fuse and split rather than coalescing into a single condensate, whereas Nucleolin-containing and ternary condensates fuse into one dominant cluster. These results reveal a molecular mechanism, grounded in sequence-encoded, RNA-controlled fusion dynamics, by which nucleolar condensates conserve a controlled, non-coalescing size despite their liquid-like character.

biophysics↗

bioRxiv2026

MYC overexpression drives poor prognosis and differential sensitivity to treatments according to TP53 status in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm with very heterogeneous clinical and biological behavior. Among molecular variables, TP53 alterations are well-established adverse prognostic markers; however, MYC activation, which has been linked to disease progression, has not been completely defined in terms of clinical and biological impact, particularly in relation to TP53 status. Here, we investigated the effects of MYC overexpression according to TP53 status using clinical and transcriptomic data from CLL patients and novel cellular models. CLL patients with TP53WT and MYC overexpression exhibited significantly shorter time to first treatment and overall survival, indicating an aggressive disease course comparable to that of patients with TP53 alterations. Consistently, MYC overexpression in in vitro TP53WTmodels was associated with increased proliferation, enrichment of AKT/mTOR signaling and upregulation of genes involved in leukemogenesis and tumor progression such as FOXO6. Moreover, MYC overexpression was associated with increased sensitivity to venetoclax in TP53WT cells. By contrast, the concurrence of MYC overexpression and TP53 dysfunction conferred resistance to conventional CLL therapies such as BCL2 or BTK inhibitors. Of note, we identified a glycolysis inhibitor, in monotherapy or combined with BKT inhibitors, as a potential therapeutic strategy for CLL patients harboring MYC overexpression and TP53 alterations.

cancer biology↗

bioRxiv2024

The mechanoreceptor PIEZO1 is a novel oncogene in glioma by promoting astrocyte reactivity

Glioblastoma is the most common and aggressive brain tumour in adults. Despite advances in its molecular characterization, there is a gap-of-knowledge in the identification of bona fide drivers and potential therapeutic targets that could change the clinical picture. Mechanoreception, the sensing of mechanical cues by cells, has proven to be an important factor in cell biology, particularly in cancer. Piezo1 is a mechanoreceptor found in all cells and seems to play a role in different cancer types, such as gastric, breast or lung cancer. However, there is still lack of understanding about its role in the onset and progression of glioblastoma. Here, we show that Piezo1 acts as an oncogene in glioma by potentially promoting chronic astrocyte reactivity. We developed a novel transgenic murine model of Piezo1 overexpression in astrocytes. These animals had a significant reduction in overall survival and developed glioma with a penetrance of 30%. We also developed a PIEZO1-overexpressing U251 cell line and found that it had a more aggressive and reactive-like phenotype. Finally, we correlated the levels of PIEZO1 with the clinical outcome of a cohort of glioblastoma patients and observed that PIEZO1 is a biomarker of worse prognosis. However, PIEZO1 only correlated with worse prognosis in male patients, suggesting a sexual dimorphism. In conclusion, we identified Piezo1 as a bona fide driver of glioma, revealing its implication in astrocyte reactivity and identifying it as a biomarker for glioma in the clinic.

cancer biology↗

bioRxiv2023

The nucleolar aberrancies that drive ribosome impairment induced by RNA binding proteins are hallmarks of aging

The nucleolus is a dynamic structure where ribosome subunits are produced. Indeed, nucleoli respond to any change in cellular homeostasis by altering the rate of ribosome biogenesis, thus working as a stress sensor. Therefore, an imbalance in ribosome biogenesis promotes changes in morphology and function and can evoke a nucleolar stress response. Changes in the structure and composition of nucleoli impair ribosome biogenesis and have been described as nucleolar stress, a mechanism related to aging and cancer. Here, we show the role of the RNA binding protein Hnrnpk in nucleolar dynamics and ribosome function. Hnrnpk is a ribonucleoprotein in charge of escorting nascent transcripts to its processing and nuclear export to ribosomes. When Hnrnpk is overexpressed, the nucleolus is altered and shows stress-like phenotype, with accumulation and delocalization of components such as Ncl, driving ribosome biogenesis impairment and halting protein translation. Nucleolin haploinsufficiency is correlated with enlarged nucleoli, increased ribosome components and translation and induces a reduction in lifespan. Thus, gain of Ncl generated by Hnrnpk overexpression can cause ribosome biogenesis defects associated with ribosome impairment leading to ribosomopathies and bone marrow failure syndrome. Aging and bone marrow failure share common biological hallmarks. Indeed, Hnrnpk overexpression and nucleolar stress trigger cell cycle arrest and senescence of the cells, a feature of both processes. Together, these findings support the idea that nucleolar abnormalities contribute to ribosome impairment, thus triggering the onset of hematopoiesis and the aging process. Here, we decipher a novel master regulator of this mechanism: Hnrnpk.

molecular biology↗

bioRxiv2023

The proton-activated receptor TDAG8 is upregulated in oligodendrocytes during maturation and under acidic conditions.

Acidosis is one of the hallmarks of demyelinating central nervous system (CNS) lesions in multiple sclerosis (MS). Response to acidic pH is primarily mediated by a family of G protein-coupled proton-sensing receptors: OGR1, GPR4, and TDAG8. These receptors are inactive at alkaline pH, while at acidic pH they are maximally activated. Genome-wide association studies identified a locus within the TDAG8 gene to be associated with several autoimmune diseases including MS. Notably, we here found that TDAG8 expression is upregulated in MS plaques which prompted us to explore the expression and function of TDAG8 in the CNS in human MO3.13 oligodendrocytes in vitro and in vivo in the lipopolysaccharide-induced neuroinflammation model. We found that TDAG8 is upregulated in maturing oligodendrocytes and temporarily under acidic conditions. Acidic pH also induces oligodendrocyte branching, inhibits chemotaxis and affects the expression of oligodendrocyte maturation markers, PDGFR and MBP in vitro. Even though myelination was not affected in the adult TDAG8-deficient mice, the expression of human and murine TDAG8 was strongly regulated upon inflammation in vivo in the brain and in vitro in lipopolysaccharide and pro-inflammatory cytokine-treated oligodendrocytes. Together these findings point toward a potential role of TDAG8 in oligodendrocyte biology, neuroinflammation and pathophysiology of MS and provide new directions for further scientific enquiry.

neuroscience↗