Biology subjects

Sheraz, S.

Publications and source records attributed to Sheraz, S..

3 recordsLinked to original sources

bioRxiv2024

SARS-CoV-2 3CLPro Dihedral Angles Reveal Allosteric Signaling

In allosteric proteins, identifying the pathways that signals take from allosteric ligand-binding sites to enzyme active sites or binding pockets and interfaces remains challenging. This avenue of research is motivated by the goals of understanding particular macromolecular systems of interest and creating general methods for their study. An especially important protein that is the subject of many investigations in allostery is the SARS-CoV-2 main protease (Mpro), which is necessary for coronaviral replication. It is both an attractive drug target and, due to intense interest in it for the development of pharmaceutical compounds, a gauge of the state-of-the-art approaches in studying protein inhibition. Here we develop a computational method for characterizing protein allostery and use it to study Mpro. We propose a role of the proteins C-terminal tail in allosteric modulation and warn of unintuitive traps that can plague studies of the role of protein dihedrals angles in transmitting allosteric signals.

biophysics↗

bioRxiv2023

Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signalling and clinical traits

CTNNB1, the gene encoding {beta}-catenin, is a frequent target for oncogenic mutations activating the canonical Wnt signalling pathway, typically via missense mutations within a degron hotspot motif in exon 3. Here, we combine saturation genome editing with a fluorescent reporter assay to quantify signalling phenotypes for all 342 missense mutations in the mutation hotspot, including 74 recurrent mutations reported in over 6000 tumours. Our data define the genetic requirements for {beta}-catenin degron function and reveal diverse levels of signal activation among known driver mutations. Tumorigenesis in different human tissues involves selection for CTNNB1 mutations spanning distinct ranges of effect size. In hepatocellular carcinoma, mutations that activate {beta}-catenin relatively weakly are associated with worse prognosis compared to stronger activating mutations, despite greater immune cell infiltration in the tumour microenvironment. Our work therefore provides a resource to understand mutational diversity within a pan-cancer mutation hotspot, with potential implications for targeted therapy.

cancer biology↗

bioRxiv2021

Subcellular dynamics studies reveal how tissue-specific distribution patterns of iron are established in developing wheat grains

Understanding iron trafficking in plants is key to enhancing the nutritional quality of crops. Due to the difficulty of imaging iron in transit, little is known about iron translocation and distribution in developing seeds. A novel approach, combining 57Fe isotope labelling and NanoSIMS, was used to visualize iron translocation dynamics at the subcellular level in wheat grain, Triticum aestivum L. We were able to track the main route of iron from maternal tissues to the embryo through different cell types. Further evidence for this route was provided by genetically diverting iron into storage vacuoles, as confirmed by histological staining and TEM-EDS. Virtually all iron was found in intracellular bodies, indicating symplastic rather than apoplastic transport. Aleurone cells contained a new type of iron body, highly enriched in 57Fe, and most likely represents iron-nicotianamine being delivered to phytate globoids. Correlation with tissue-specific gene expression provides an updated model of iron homeostasis in cereal grains with relevance for future biofortification efforts.

plant biology↗