Biology subjects

Nessler, S.

Publications and source records attributed to Nessler, S..

4 recordsLinked to original sources

bioRxiv2025

Molecular and functional dissection of the AP2-I/BDP1 transcriptional complex of the malaria parasite reveals a role beyond the red blood cell stages

The transcription factor AP2-I and the bromodomain protein BDP1 of the malaria parasite bind upstream of several genes implicated in red blood cell invasion. Here, we demonstrate that they form a complex and that AP2-I recruits BDP1 to the target genes. The ACDC domain of AP2-I interacts with a BDP1 region called BAAS, located between the ankyrin and the bromodomain. The ankyrin, in turn, binds to a conserved AP2-I specific region called ASAIR. Three of the interacting domains are parasite-specific, allowing inhibition without affecting the host. We further show that AP2-I is essential for asexual blood stage development, playing multiple roles, and that AP2-I and BDP1 function beyond invasion, binding to the promoters of the gametocytogenesis regulators gdv1 and ap2-g, suggesting a role for the AP2-I/BDP1 complex in parasite sexual commitment. Overall, our study highlights the essential and unique nature of the AP2-I/BDP1 complex and its potential as a novel antimalarial drug target. Author summaryThe transcription factor AP2-I and the bromodomain protein BDP1 of the malaria parasite have previously been shown to be implicated in red blood cell invasion by the human malaria parasite. Here we show that they form a complex and identify the interacting domains on each protein. Three of these are parasite-specific, allowing inhibition without affecting the human host. We also show that AP2-I is essential for parasite survival in the blood and that the protein is implicated in other processes beyond red blood cell invasion. Namely, AP2-I, but also BDP1, bind to the promoters of the gametocytogenesis regulators gdv1 and ap2-g, suggesting a role for the AP2-I/BDP1 complex in parasite sexual commitment, without which the parasite cannot be transmitted.

microbiology↗

bioRxiv2024

Structural characterization of the ACDC domain from ApiAP2 proteins of the malaria parasite

The Apicomplexan AP2 (ApiAP2) proteins are the best characterized family of DNA-binding proteins in the malaria parasite. Apart from the AP2 DNA-binding domain, there is little sequence similarity between ApiAP2 proteins and no other functional domains have been extensively characterized. One protein domain, which is present in a subset of the ApiAP2 proteins, is the conserved AP2-coincident domain mostly at the C-terminus (ACDC domain). Here we solved for the first time the crystal structure of the ACDC domain from two distinct Plasmodium falciparum ApiAP2 proteins and one orthologue from P. vivax, revealing a non-canonical four-helix bundle. Despite little sequence conservation between the ACDC domains from the two proteins, the structures are remarkably similar and do not resemble that of any other known protein domains. Due to their unique protein architecture and lack of homologues in the human genome, we performed in silico docking calculations against a library of known antimalarial compounds and we identified a small molecule that can potentially bind to any Apicomplexan ACDC domain within a pocket highly conserved amongst ApiAP2 proteins. Inhibitors based on this compound would disrupt the function of the ACDC domain and thus of the ApiAP2 proteins containing it, providing a new therapeutic window for targeting the malaria parasite and other Apicomplexans.

biochemistry↗

bioRxiv2022

Polymerization cycle of actin homolog MreB from a Gram-positive bacterium

In most rod-shaped bacteria, the actin homologue MreB is an essential component of the protein complex effecting cell wall elongation. The polymerization cycle and filament properties of eukaryotic actin have studied for decades and are well characterized. However, purification and in vitro work on MreB proteins have proven very difficult. Current knowledge of MreB biochemical and polymerization properties remains limited and is based on MreB proteins from Gram-negative species. In this study, we report the first observation of organized filaments and the first 3D-structure of MreB from a Gram-positive bacterium. We have purified MreB from the thermophilic Geobacillus stearothermophilus and shown that it forms straight pairs of protofilaments in vitro, and that polymerization depends on the presence of both lipids and nucleotide triphosphate. Two spatially close short hydrophobic sequences mediate membrane anchoring. Importantly, we demonstrate that unlike eukaryotic actin, nucleotide hydrolysis is a prerequisite for MreB interaction with the membrane, and that binding to lipids then triggers polymerization. Based on our results, we propose a molecular model for the mechanism of MreB polymerization.

biochemistry↗

bioRxiv2021

SARS-CoV-2 mutations acquired in mink reduce antibody-mediated neutralization

Transmission of SARS-CoV-2 from humans to farmed mink was observed in Europe and the US. In the infected animals viral variants arose that harbored mutations in the spike (S) protein, the target of neutralizing antibodies, and these variants were transmitted back to humans. This raised concerns that mink might become a constant source of human infection with SARS-CoV-2 variants associated with an increased threat to human health and resulted in mass culling of mink. Here, we report that mutations frequently found in the S proteins of SARS-CoV-2 from mink were mostly compatible with efficient entry into human cells and its inhibition by soluble ACE2. In contrast, mutation Y453F reduced neutralization by an antibody with emergency use authorization for COVID-19 therapy and by sera/plasma from COVID-19 patients. These results suggest that antibody responses induced upon infection or certain antibodies used for treatment might offer insufficient protection against SARS-CoV-2 variants from mink.

molecular biology↗