Biology subjects

Daus, N.

Publications and source records attributed to Daus, N..

4 recordsLinked to original sources

bioRxiv2025

Ca2+-calmodulin regulates Kv7.1 channel gating by allosterically interfering with its inactivation path

Like in many voltage-gated K+ channels (Kv), inactivation of the cardiac Kv7.1 channel is voltage-dependent but does not exhibit the hallmarks of N-type or C-type mechanisms. This peculiar inactivation is observed in wild-type channels and is exacerbated in many Kv7.1 mutations triggering cardiac arrhythmias. Previously, we showed that Kv7.1 inactivation could strikingly be prevented by Ca2+-calmodulin (Ca2+-CaM). Thus, how can Ca2+-CaM, localized at the channel inner boundaries, prevent inactivation that occurs distantly at the outer pore region and converges to the selectivity filter? Here, using network analysis, molecular dynamics simulations, and electrophysiology, we identify the inactivation paths coupling the voltage sensor domain to the selectivity filter, involving helices S1 and S6, and the P-Helix, which represents the underlying mechanism of Kv7.1 inactivation. Moreover, our data reveal the allosteric coupling mechanisms by which Ca2+-CaM signals interfere with the inactivation paths and prevent channel inactivation.

biophysics↗

bioRxiv2025

ZNF512B associates with mitotic spindles, regulates metaphase exit and is crucial for stem cell differentiation

Zinc finger proteins are a large family of DNA-binding factors that play key roles in diverse cellular processes including gene regulation, RNA metabolism and cell cycle control. The zinc finger protein ZNF512B has recently been implicated in chromatin organization and transcriptional repression through its direct interaction with the nucleosome remodeling and deacetylase (NuRD) complex, its DNA-binding ability, and its association with the histone variant H2A.Z. Here, we uncover a previously unrecognized role for ZNF512B that is independent of both its zinc finger domains and NuRD association. We identify ZNF512B as a spindle-associated factor that regulates progression through mitosis, specifically controlling metaphase exit. ZNF512Bs N-terminal internal region, which contains 25 repeats of a six-residue motif predicted to form a {beta}-helix structure, is required and sufficient for its spindle interaction. Elevated ZNF512B levels result in a profound metaphase arrest that is ultimately lethal, a phenotype arising from the combined activity of its spindle-binding and chromatin-tethering functions. Conversely, ZNF512B depletion accelerates stem cell proliferation, impairs differentiation, and upregulates genes linked to cell cycle progression. Our findings position ZNF512B as a multifunctional protein that acts as a transcriptional repressor, a chromatin aggregator and a novel metaphase exit regulator through spindle fiber binding.

molecular biology↗

bioRxiv2023

ZNF512B binds RBBP4 via a variant NuRD interaction motif and aggregates chromatin in a NuRD complex-independent manner

The evolutionarily conserved histone variant H2A.Z plays a crucial role in various DNA-based processes but the underlying mechanisms by which it acts are not completely understood. Recently, we identified the zinc finger protein ZNF512B as an H2A.Z-, HMG20A- and PWWP2A-associated protein. Here, we report that ZNF512B binds the nucleosome remodeling and deacetylase (NuRD) complex. We discover a conserved amino acid sequence within ZNF512B that resembles the NuRD-interaction motif (NIM) previously identified in FOG-1 and other transcriptional regulators. By solving the crystal structure of this motif bound to the NuRD component RBBP4 and by applying several biochemical assays we demonstrate that this internal NIM is both necessary and sufficient for robust NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as a repressor of gene expression that can act in both NuRD-dependent and -independent ways. Surprisingly, high levels of ZNF512B expression lead to nuclear protein and chromatin aggregation foci that form independent of the interaction with the NuRD complex but depend on the zinc finger domains of ZNF512B. Our study has implications for diseases in which ZNF512B expression is deregulated, such as cancer and neurodegenerative diseases, and hint at the existence of more proteins as potential NuRD interactors.

molecular biology↗

bioRxiv2022

The H2A.Z.1/PWWP2A/NuRD-associated protein HMG20A controls early head and heart developmental transcription programs

Abstract/SummarySpecialized chromatin-binding proteins are required for DNA-based processes during development. We recently established PWWP2A as direct histone variant H2A.Z interactor involved in mitosis and cranial-facial development. Here, we identify the H2A.Z/PWWP2A-associated protein HMG20A as part of several chromatin-modifying complexes including NuRD, and show that it localizes to genomic regulatory regions. Hmg20a depletion causes severe head and heart developmental defects in Xenopus laevis. Our data indicate that craniofacial malformations are caused by defects in neural crest cell (NCC) migration and cartilage formation. These developmental defects are pheno-copied in HMG20A-depleted mESCs, which show inefficient differentiation into NCCs and cardiomyocytes (CMs). Accordingly, loss of HMG20A caused striking deregulation of transcription programs involved in epithelial- mesenchymal transition (EMT) and cardiac differentiation, thereby providing insights into the regulatory circuits controlled by HMG20A. Collectively, our findings implicate HMG20A as part of the H2A.Z/PWWP2A/NuRD-axis and reveal it as a key modulator of the intricate developmental transcription programs that guide NCC and cardiomyocyte differentiation.

molecular biology↗