Biology subjects

Vigneron, S.

Publications and source records attributed to Vigneron, S..

5 recordsLinked to original sources

bioRxiv2026

FAM122A inhibition of PP2A-B55 through a bipartite binding mechanism

FAM122A regulates cell cycle progression through inhibition of the PP2A-B55 phosphoprotein phosphatase. Recent structural work has uncovered helical elements in the N-terminus of FAM122A as binding determinants for PP2A-B55 but whether FAM122A inhibition towards PP2A-B55 is regulated is presently unclear. To address this we performed a systematic analysis of the PP2A-B55 interaction with FAM122A in cells uncovering a novel region in the C-terminus of FAM122A, spanning residues 150-170, required for binding. This C-terminal region and the N-terminal helices are both required for efficient binding to PP2A-B55 suggesting a bipartite binding mechanism. We perform amino acid resolution scans of FAM122A 150-170 uncovering several residues in this region contributing to binding including the conserved Ser158, a reported phosphorylation site. We show that Ser158 is important for PP2A-B55 inhibition in human cells as well as efficient stimulation of mitotic entry in Xenopus laevis egg extracts. In human cells and in Xenopus laevis Ser158 phosphorylation is regulated with increased occupancy correlating with cell cycle stages requiring PP2A-B55 inhibition. Collectively our work uncovers novel aspects of FAM122A interaction with PP2A-B55 and provides a possible mechanism for how the inhibitory activity of FAM122A can be regulated during the cell cycle.

cell biology↗

bioRxiv2025

Greatwall depletion from Xenopus oocytes reveals a key role of the cyclin B/CDK1-PP2A-B55 balance in the coordination of meiotic events

Meiotic progression relies on maintaining a precise balance between cyclin B/CDK1 activity and the phosphatase PP2A-B55. The latter is negatively regulated by the Greatwall kinase (Gwl). In Xenopus oocytes, we show that the loss of Gwl and the subsequent hyperactivation of PP2A-B55 severely disrupt the transition from meiosis I to meiosis II. This disruption prevents phosphorylation of both Wee1/Myt1 and the APC/C complex, thereby blocking APC/C activation. As a consequence, APC/C remains inactive during the MI-MII transition, which impairs cyclin degradation and the partial CDK1 inactivation that is normally required at this stage. Additionally, the mos-MAPK-Rsk1/2 pathway fails to activate due to insufficient Mos accumulation, thereby preventing metaphase II arrest. Finally, the lack of APC/C activation during meiosis I inhibits the degradation of its inhibitor Erp1, revealing a critical feedback loop between APC/C and Erp1. Overall, our findings reveal that Gwl is a key coordinator of both meiotic divisions, acting through dual regulation of APC/C and the Mos/MAPK/Rsk1/2 pathways by modulating PP2A-B55 activity.

biochemistry↗

bioRxiv2023

Cyclin A/cdk activity and FAM122A-dependent inhibition of PP2A-B55 are essential to trigger mitosis.

Entry into mitosis has been classically attributed to the activation of cyclin B/cdk1 amplification loop by a partial pool of this kinase that becomes active at the end of G2. However, how this pool is activated is still unknown. Here we discovered a new role of the recently identified PP2A-B55 inhibitor FAM122A in triggering mitotic entry. Accordingly, the depletion of the orthologue of FAM122A in C. elegans, prevents entry into mitosis in germline stem cells. Moreover, our data in Xenopus egg extract strongly supports that FAM122A-dependent inhibition of PP2A-B55 could be the initial event promoting mitotic entry. The inhibition of this phosphatase allows the subsequent phosphorylation of first mitotic substrates by cyclin A/cdk resulting in cyclin B/cdk1 and Greatwall (Gwl) activation. However, interestingly, from Gwl activation, Arpp19/ENSA become phosphorylated and compete with FAM122A promoting its dissociation from PP2A-B55 and taking over its inhibition until the end of mitosis.

cell biology↗

bioRxiv2022

Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Antiviral therapeutics to treat SARS-CoV-2 are much desired for the on-going pandemic. A well-precedented viral enzyme is the main protease (MPro), which is now targeted by an approved drug and by several investigational drugs. With the inevitable liabilities of these new drugs, and facing viral resistance, there remains a call for new chemical scaffolds against MPro. We virtually docked 1.2 billion non-covalent and a new library of 6.5 million electrophilic molecules against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 M and 20 M, respectively. Several series were optimized, resulting in inhibitors active in the low micromolar range. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. Together, these compounds reveal new chemotypes to aid in further discovery of MPro inhibitors for SARS-CoV-2 and other future coronaviruses.

biophysics↗

bioRxiv2020

The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals a new Arpp19/PP2A-B55 feedback loop

Arpp19 is a potent inhibitor of PP2A-B55 that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by Greatwall on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as an "unfair" competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signaling mechanism is elusive. Here, we characterized the molecular determinants conferring slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we showed that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discovered a double feed-back loop between these two phospho-sites which is essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division.

developmental biology↗