Biology subjects

El Marjou, A.

Publications and source records attributed to El Marjou, A..

3 recordsLinked to original sources

bioRxiv2025

CARM1-mediated methylation controls interactions of ALIX with key partners important for cytokinesis

CARM1 is an arginine methyltransferase with a well-established role in regulating gene expression, but its cytoplasmic functions remain largely uncharacterized. Here, we identified ALIX, a protein acting with the ESCRT-III machinery in numerous membrane remodeling events, as a main cytoplasmic partner and a relevant substrate of CARM1. We demonstrate that CARM1 methylates arginine residues within the proline-rich motif of ALIX. At the molecular level, ALIX methylation impairs SH3-dependent association with CD2AP, CIN85, and endophilin-A2 that are required for cytokinesis. Using a mutant of ALIX that is unable to bind these proteins, we further show that these interactions are essential for ALIX functions during cytokinesis. Altogether, this work highlights the significance of arginine methylation as a regulatory post-translational modification important for the final step of cell division, by modulating interactions between proline-rich domains and their SH3-containing partners.

cell biology↗

bioRxiv2022

Nucleotide-free structures of Kif20A illuminate the atypical allostery in this mitotic kinesin-6

KIF20A is a critical kinesin for cell division and a promising anti-cancer drug target. The mechanisms underlying its cellular roles remain elusive. Interestingly, unusual coupling between the nucleotide- and microtubule-binding sites of this kinesin-6 has been reported but little is known about how its divergent sequence leads to atypical motility properties. We present here the first high-resolution structure of its motor domain that delineates the highly unusual structural features of this motor, including a long L6 insertion that integrates into the core of the motor domain and that drastically affects allostery and ATPase activity. Together with the high-resolution cryo-EM microtubule-bound KIF20A structure that reveal the microtubule-binding interface, we dissect the peculiarities of the KIF20A sequence that work to favor fast dissociation of ADP, particularly in contrast to other kinesins. Structural and functional insights from the KIF20A pre-power stroke conformation thus highlight the role of extended insertions in shaping the motor mechanochemical cycle. Essential for force production and processivity is the length of the neck linker in kinesins. We highlight here the role of the sequence preceding the neck linker in controlling its backward docking and show that a neck linker 4-times longer than kinesin-1 is required for the activity of this motor.

biochemistry↗

bioRxiv2018

Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1

The BRCA2 tumor suppressor protein is involved in the maintenance of genome integrity through its role in homologous recombination. In mitosis, BRCA2 is phosphorylated by Polo-like kinase 1 (PLK1). Here we describe how this phosphorylation contributes to the control of mitosis. We identified two highly conserved phosphorylation sites at S193 and T207 of BRCA2. Phosphorylated-T207 is a bona fide docking site for PLK1 as illustrated by the crystal structure of the BRCA2 peptide bound to PLK1 Polo-box domain. We found that BRCA2 bound to PLK1 forms a complex with the phosphatase PP2A and phosphorylated-BUBR1. Reducing BRCA2 binding to PLK1, as observed in BRCA2 breast cancer variants S206C and T207A, alters the tetrameric complex resulting in misaligned chromosomes, faulty chromosome segregation and aneuploidy. We thus reveal a direct role of BRCA2 in the alignment of chromosomes, distinct from its DNA repair function, with important consequences on chromosome stability. These findings may explain in part the aneuploidy observed in BRCA2-mutated tumors.

cell biology↗