Biology subjects

Hajsmanova, H.

Publications and source records attributed to Hajsmanova, H..

2 recordsLinked to original sources

bioRxiv2026

NOTCH1-specific phosphorylation of S1970 by Casein Kinase 1 is required for NOTCH1 transcriptional competence and signaling activity in vivo

The Notch and Wnt/{beta}-catenin signaling pathways are essential regulators for cell-fate decisions, cellular patterning, and tissue homeostasis. Multiple studies point to their orchestrated role during development, but the molecular mechanism of the protein-protein crosstalk is largely unknown. Here, after screening effects of Wnt/{beta}-catenin component loss on NOTCH1 protein, we identify Casein Kinase 1 (CK1) as a positive regulator of NOTCH1 activity in vitro and in vivo. We demonstrate that CK1 associates with NOTCH1 and that its kinase activity is required to sustain Notch-driven transcription. Using UltraID proximity-assay, we revealed that CK1 is required for the NOTCH1 interactivity with transporter proteins, and MAML1 both prior and after ligand-induced activation. Combining structural modelling, NMR, and mass spectrometry, we identified Serine 1970 (S1970) as a previously unreported residue within the Notch1 Intracellular Domain (N1ICD) essential for its signaling competence. Our modeling predicts that the phosphorylation of S1970 facilitates an intra-domain conformational switch with R1937 and R1962 residues altering the assembly of the N1ICD-MAML1-RBPJk transcriptional complex. Finally, we demonstrate the biological significance of N1ICD S1970 in vivo using Xenopus laevis axis-duplication rescue assay. Our results establish CK1 as a key positive mediator of the Notch receptor transcriptional activity.

cell biology↗

bioRxiv2026

Bardet-Biedl Syndrome 1 Mutations Differentially Impact BBSome Integrity and its Function in Ciliary Trafficking

Bardet-Biedl Syndrome (BBS) is a pleiotropic ciliopathy marked by retinal degeneration, obesity, polydactyly, renal and reproductive anomalies, and cognitive impairment. BBS1, the most frequently mutated gene in BBS, encodes a key component of the BBSome complex, which is essential for ciliary membrane trafficking. Although BBS1 is known to be essential for proper BBSome function, the effects of disease-associated BBS1 variants on its activity remain incompletely understood. In this study, we examined how patient-derived BBS1 mutations affect BBSome integrity and its role in cargo transport within primary cilia. Our results show that particular BBS1 mutations interfere with distinct stages of BBSome assembly and trafficking. While M390R disrupts initial pre-BBSome assembly at pericentriolar satellites, E224K impairs both the maturation of the pre-BBSome into the BBSome and its movement from pericentriolar satellites to the cilium. In contrast, the R160Q variant preserves BBSome assembly and permits its localization to cilia. It specifically weakens the BBSome-GPCR interaction mediated by TOM1L2, resulting in defective GPR161 export and increased ciliary IFT turnover. Overall, our study establishes a mechanistic framework linking specific BBS1 mutations to distinct defects in BBSome assembly and function. This framework defines functional classes of BBS1 variants and provides deeper insight into the molecular mechanism and severity of Bardet-Biedl Syndrome.

cell biology↗