Biology subjects

Zaman, M.

Publications and source records attributed to Zaman, M..

3 recordsLinked to original sources

bioRxiv2021

Heparin promotes fibrillation of most phenol soluble modulin peptides from S. aureus: a possible strengthening of the bacterial biofilm

Phenol soluble modulins (PSMs) are virulence peptides secreted by different Staphylococcus aureus strains. In addition, PSMs are able to form amyloid fibrils which may strengthen the biofilm matrix. The highly sulfated glycosaminoglycan heparin promotes S.aureus infection but the basis for this is unclear. We hypothesized that heparin promotes PSM fibrillation and in this way aids bacterial colonization. Here we address this hypothesis using a combination of different biophysical techniques along with peptide microarrays. We find that heparin accelerates fibrillation of all -PSMs (except PSM2) and {delta}-toxin, but inhibits {beta}-PSMs fibrillation by blocking nucleation. Given that S. aureus secretes higher levels of -PSMs than {beta}-PSMs peptidess, heparin is likely to overall promote fibrillation. Heparin binding is driven by multiple positively charged lysine residues in -PSMs and {delta}-toxins, whose removal strongly reduces affinity. Binding of heparin does not alter the final fibril conformation. Rather, heparin provides a scaffold to catalyze or inhibit fibrillation. Our findings suggest that heparin may strengthen bacterial biofilm through increased PSM fibrillation. O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/434294v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@99c3bdorg.highwire.dtl.DTLVardef@101d9b6org.highwire.dtl.DTLVardef@7c4058org.highwire.dtl.DTLVardef@1647eca_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2021

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

genetics↗

bioRxiv2020

Cross-talk between individual phenol soluble modulins in S. aureus biofilm formation

The infective ability of the opportunistic pathogen Staphylococcus aureus is associated with biofilm mediated resistance to host immune response and even disinfectants and indeed S. aureus is recognized as the most frequent cause of biofilm associated infections. Phenol-soluble modulin (PSM) peptides serve various roles in pathogenicity while also comprising the structural scaffold of S. aureus biofilms through self-assembly into functional amyloids, but the role of the individual PSMs during biofilm formation remains poorly understood and the molecular pathways of PSM self-assembly have proved challenging to identify. Here, we show a high degree of cooperation between individual PSMs during the formation of functional amyloids in biofilm formation. The fast aggregating PSM3 initiates the aggregation by forming unstable aggregates capable of seeding the formation of aggregates by other PSM peptides into the formation of stable amyloid structures. Using chemical kinetics along with spectroscopic techniques we dissect the molecular mechanism of aggregation of the individual peptides to show that PSM1, PSM3 and PSM{beta}1 display secondary nucleation whereas {beta}PSM2 aggregates through primary nucleation and elongation. Our findings suggest that the various PSMs have evolved to ensure fast and efficient biofilm formation through cooperation between individual peptides.

biophysics↗