Biology subjects

Coste, F.

Publications and source records attributed to Coste, F..

6 recordsLinked to original sources

bioRxiv2026

A new class of inherently efficient SUMOylation substrates

SUMOylation is an essential eukaryotic ubiquitin-like post-translational modification that plays a central role in the regulation of various nuclear processes and stress responses. It canonically occurs at lysine residues within {Psi}KXE consensus motifs that lie in intrinsically disordered regions or loops and interact specifically with the SUMO-conjugating E2 enzyme UBC9. However, many detected SUMOylation sites are found within structured domains, and it remains unclear how these are recognised by UBC9. Here, we investigated the SUMOylation of Lys43 in the BTB domain of human ZBTB38 (ZBTB38BTB), a lysine located within a rigid {beta}-sheet. By combining X-ray crystallography, structural prediction, and in-vitro UBC9 interaction and SUMOylation assays, we show that ZBTB38BTB possesses a dedicated surface that recapitulates the spatial arrangement of residues found in canonical linear consensus motifs. This surface binds UBC9 with mid-micromolar affinity and is predicted to position Lys43 in its active site for efficient SUMOylation. Structural modelling and sequence analyses suggest that this property is shared by BTB domains of five members (10%) of the ZBTB-protein family across vertebrates, revealing a previously unrecognised property of a subset of ZBTBBTB domains. Kinetic analyses reveal that, under the reaction conditions used, the catalytic efficiency of ZBTB38BTB and ZBTB33BTB SUMOylation are closely comparable to that of the C-terminal domain of RANGAP1, the best-characterised and most efficiently SUMOylated substrate known. This defines a new class of inherently efficient, E3 ligase-independent SUMOylation substrates beyond RANGAP1 and suggests that structural pre-organisation of the acceptor lysine and its environment may promote productive UBC9 engagement. Lastly, we demonstrate the presence of higher-molecular-weight, modified forms of ZBTB38 in human cells, consistent with SUMOylation. Together, these results provide a biochemical basis for interpreting existing and designing future studies on the functional impact of ZBTB SUMOylation. More broadly, our findings offer insights into the determinants of efficient SUMOylation, and may facilitate the identification of further inherently efficient targets, and, potentially, the design of SUMOylation modulators.

biochemistry↗

bioRxiv2025

FUSE-PhyloTree: Linking functions and sequence conservation modules of a protein family through phylogenomic analysis

FUSE-PhyloTree is a phylogenomic analysis software for identifying local sequence conservation associated with the different functions of a multi-functional (e.g., paralogous or multi-domain) protein family. FUSE-PhyloTree introduces an original approach that combines advanced sequence analysis with phylogenetic methods. First, local sequence conservation modules within the family are identified using partial local multiple sequence alignment. Next, the evolution of the detected modules and known protein functions is inferred within the familys phylogenetic tree using three-level phylogenetic reconciliation and ancestral state reconstruction. As a result, FUSE-PhyloTree provides a gene tree annotated with both predicted sequence modules and ancestral gene functions, enabling the association of functions with specific sequence regions based on their co-emergence. Availability and ImplementationFUSE-PhyloTree is provided as Docker and Singularity images including all the required software tools. Images, source code, test data, and documentation are available at https://github.com/OcMalde/fuse-phylotree. Supplementary InformationAn illustration of the application of FUSE-PhyloTree to the fibulin protein family is presented in the Appendix.

bioinformatics↗

bioRxiv2021

Cryo-EM structure of the transcription termination factor Rho from Mycobacterium tuberculosis reveals mechanism of resistance to bicyclomycin

The bacterial Rho factor is a ring-shaped motor triggering genome-wide transcription termination and R-loop dissociation. Rho is essential in many species, including in Mycobacterium tuberculosis where rho gene inactivation leads to rapid death. Yet, the M. tuberculosis Rho [MtbRho] factor displays poor NTPase and helicase activities, and resistance to the natural Rho inhibitor bicyclomycin [BCM] that remain unexplained. Here, we address these unusual features by solving the cryo-EM structure of MtbRho at 3.3 [A] resolution, providing a new framework for future antibiotic development. The MtbRho hexamer is poised into a pre-catalytic, open-ringed state wherein specific contacts stabilize ATP in intersubunit ATPase pockets, thereby explaining the cofactor preference of MtbRho. We reveal a leucine-to-methionine substitution that creates a steric bulk in BCM binding cavities near the positions of ATP {gamma}-phosphates, and confers resistance to BCM at the expense of motor efficiency.

molecular biology↗

bioRxiv2020

PPalign: Optimal alignment of Potts models representing proteins with direct coupling information

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSTo assign structural and functional annotations to the ever increasing amount of sequenced proteins, the main approach relies on sequence-based homology search methods, e.g. BLAST or the current state-of-the-art methods based on profile Hidden Markov Models (pHMM), which rely on significant alignments of query sequences to annotated proteins or protein families. While powerful, these approaches do not take coevolution between residues into account. Taking advantage of recent advances in the field of contact prediction, we propose here to represent proteins by Potts models, which model direct couplings between positions in addition to positional composition, and to compare proteins by aligning these models. Due to non-local dependencies, the problem of aligning Potts models is hard and remains the main computational bottleneck for their use. ResultsWe introduce here an Integer Linear Programming formulation of the problem and PPalign, a program based on this formulation, to compute the optimal pairwise alignment of Potts models representing proteins in tractable time. The approach is assessed with respect to a non-redundant set of reference pairwise sequence alignments from SISYPHUS benchmark which have lowest sequence identity (between 3% and 20%) and enable to build reliable Potts models for each sequence to be aligned. This experimentation confirms that Potts models can be aligned in reasonable time (1'37'' in average on these alignments). The contribution of couplings is evaluated in comparison with HHalign and PPalign without couplings. Although Potts models were not fully optimized for alignment purposes and simple gap scores were used, PPalign yields a better mean F1 score and finds significantly better alignments than HHalign and PPalign without couplings in some cases. ConclusionsThese results show that pairwise couplings from protein Potts models can be used to improve the alignment of remotely related protein sequences in tractable time. Our experimentation suggests yet that new research on the inference of Potts models is now needed to make them more comparable and suitable for homology search. We think that PPaligns guaranteed optimality will be a powerful asset to perform unbiased investigations in this direction.

bioinformatics↗

bioRxiv2020

ComPotts: Optimal alignment of coevolutionary models for protein sequences

To assign structural and functional annotations to the ever increasing amount of sequenced proteins, the main approach relies on sequence-based homology search methods, e.g. BLAST or the current state-of-the-art methods based on profile Hidden Markov Models (pHMMs), which rely on significant alignments of query sequences to annotated proteins or protein families. While powerful, these approaches do not take coevolution between residues into account. Taking advantage of recent advances in the field of contact prediction, we propose here to represent proteins by Potts models, which model direct couplings between positions in addition to positional composition. Due to the presence of non-local dependencies, aligning two Potts models is computationally hard. To tackle this task, we introduce an Integer Linear Programming formulation of the problem and present ComPotts, an implementation able to compute the optimal alignment of two Potts models representing proteins in tractable time. A first experimentation on 59 low sequence identity pairwise alignments, extracted from 3 reference alignments from sisyphus and BaliBase3 databases, shows that ComPotts finds better alignments than the other tested methods in the majority of these cases.

bioinformatics↗

bioRxiv2018

Fibrocyte accumulation in bronchi: a cellular hallmark of COPD

BackgroundThe remodeling mechanism and cellular players causing persistent airflow limitation in chronic obstructive pulmonary disease (COPD) remain largely elusive. We have recently demonstrated that circulating fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are increased in COPD patients during an exacerbation. It remains, however, unclear, whether fibrocytes are present in bronchial tissue of COPD patients.\n\nObjectiveWe aimed to quantify fibrocytes density in bronchial specimens from both control subjects and COPD patients, and to define associations with clinical, functional and computed tomography relevant parameters.\n\nMethods17 COPD patients and 25 control subjects with normal lung function testing and no chronic symptoms, all of them requiring thoracic surgery, were recruited. LFT and CT-scan were performed before surgery. Using co-immunostaining and image analysis, we identify CD45+ FSP1+ cells as tissue fibrocytes and quantify their density in distal and proximal bronchial specimens from the whole series.\n\nResultsHere, we demonstrate that fibrocytes are increased in both distal and proximal tissue specimens of COPD patients, compared to those of controls. The density of fibrocytes is negatively correlated with lung function parameters, such as FEV1 and FEV1/FVC, and positively with bronchial wall thickness assessed by CT scan. High density of distal bronchial fibrocytes predicts presence of COPD with a sensitivity of 83% and a specificity of 70%.\n\nConclusionsOur results thus suggest that recruitment of fibrocytes in the bronchi may participate to lung function decline during COPD progression.\n\nClinical ImplicationsHigh density of tissue fibrocytes is associated with a deteriorated lung function and an increase in airway wall thickness. A low density tissue fibrocytes virtually eliminates the presence of COPD.\n\nCapsule summaryBlood fibrocytes assessed during exacerbation is a predictor of mortality in COPD. This study shows an increase of bronchial fibrocytes, that is associated with lower lung function, increased bronchial thickness and air trapping in COPD.

physiology↗