Biology subjects

Scholes, H. M.

Publications and source records attributed to Scholes, H. M..

3 recordsLinked to original sources

bioRxiv2020

SARS-CoV-2 spike protein predicted to form stable complexes with host receptor protein orthologues from mammals, but not fish, birds or reptiles

SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.

bioinformatics↗

bioRxiv2020

CATH functional families predict protein functional sites

MotivationIdentification of functional sites in proteins is essential for functional characterisation, variant interpretation and drug design. Several methods are available for predicting either a generic functional site, or specific types of functional site. Here, we present FunSite, a machine learning predictor that identifies catalytic, ligand-binding and protein-protein interaction functional sites using features derived from protein sequence and structure, and evolutionary data from CATH functional families (FunFams). ResultsFunSites prediction performance was rigorously benchmarked using cross-validation and a holdout dataset. FunSite outperformed all publicly-available functional site prediction methods. We show that conserved residues in FunFams are enriched in functional sites. We found FunSites performance depends greatly on the quality of functional site annotations and the information content of FunFams in the training data. Finally, we analyse which structural and evolutionary features are most predictive for functional sites. AvailabilityThe datasets and prediction models are available on request. Contactc.orengo@ucl.ac.uk Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2018

Tracking dynamic changes in Alzheimer’s disease brain proteome reveals ageing-independent damage in Drosophila

Alzheimers disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Understanding the molecular pathology of AD during disease progression may identify new ways to reduce neuronal damage. Here, we present a longitudinal study tracking dynamic proteomic alterations in the brains of an inducible Drosophila melanogaster model of AD expressing the Arctic mutant A{beta}42 gene. We identified 3093 proteins from flies that were induced to express A{beta}42 and age-matched healthy controls using label-free quantitative ion-mobility data independent analysis mass spectrometry. Of these, 228 proteins were significantly altered by A{beta}42 accumulation and were enriched for AD-associated processes. Network analyses further revealed that these proteins have distinct hub and bottleneck properties in the brain protein interaction network, suggesting that several may have significant effects on brain function. Our unbiased analysis provides useful insights into the key processes governing the progression of amyloid toxicity and forms a basis for further functional analyses in model organisms and translation to mammalian systems.

biochemistry↗