Biology subjects

Sallah, S.

Publications and source records attributed to Sallah, S..

3 recordsLinked to original sources

bioRxiv2026

Prediction of pH-sensing histidine residues in human cells

Changes in pH play an important role in human physiology and cell behaviours, evidenced by studies of tissues and gene expression, and the biophysics of individual systems. Bridging between these scales to establish pH-sensing networks has only been partially explored. Here, amino acid conservation and structural context, and benchmarking with known pH-sensors, were used to predict histidine residues within the human proteome that could modulate pH-dependence. Proteins containing these histidines are enriched in many categories, most notably nucleic acid-binding and transcriptional regulation. DNA phosphate backbone interactions are proposed to play a major role in modulating some pH-sensors. Transcription factors with potential pH-sensors and the largest number of documented target genes are highlighted, including those involved in circadian and developmental processes. Certain CDK-cyclin pairs also feature, along with components of SWI/SNF and cohesin complexes. Focussing on histidines, including those that are solvent accessible in AlphaFold protomer models, this study generates benchmarked predictions for possible pH-sensors in the human proteome.

bioinformatics↗

bioRxiv2025

Computational investigation suggests that the cell adhesion sub-proteome is enriched for sites of pH-dependence and charge burial, whilst some key intracellular pathways may be shielded from pH fluctuations.

Prediction of protein pH-dependence is generally made for individual proteins or pathways, and is also increasingly being used to aid protein functional design. Combining high-throughput pKa prediction methods with AlphaFold models allows pH-dependence to be studied across a proteome. Here, two methods and a variety of features for detecting pH-dependence and charge burial that is physiologically relevant, have been applied to human proteins. Predictions are effective for a small benchmark subset of well-characterised proteins and, more broadly, identify an overlap between features associated with pH-dependence and enzymes and transporters. The most informative filters are those describing relatively buried ionisable groups, with pKas close to neutral pH and/or involvement in highly-coupled charge networks. The question is addressed of which human proteins not annotated as enzymes or transporters, are predicted to have these features of predicted pH-dependence and/or charge networking. A striking feature from gene ontology analysis of those proteins is a predicted enrichment at the cell periphery, in particular an association with cell adhesion, including protein families not currently known to exhibit pH-dependence. Gene ontology classifications that are depleted for proteins with buried charge networks and/or predicted functional pH-dependence, include some associated with ribosomal and nuclear structure. This overall result suggests a possible general resilience of some key processes to pH fluctuations, whilst not precluding specific instances where signalling pathways have evolved responses to pH changes. A drawback of the study is restriction to protomer models, thus omitting groups that mediate pH-dependence through burial at an interface. However predictions are already notable, with their details provided for experimental design.

bioinformatics↗

bioRxiv2024

Computational investigation of missense somatic mutations in cancer and potential links to pH-dependence and proteostasis

Metabolic changes during tumour development lead to acidification of the extracellular environment and a smaller increase of intracellular pH. Searches for somatic missense mutations that could reveal adaptation to altered pH have focussed on arginine to histidine changes, part of a general arginine depletion that originates from DNA mutational mechanisms. Analysis of mutations to histidine, potentially a simple route to the introduction of pH-sensing, shows no clear biophysical separation overall of subsets that are more and less frequently mutated in cancer genomes. Within the more frequently mutated subset, individual sites predicted to mediate pH-dependence upon mutation include NDST1 (a Golgi-resident heparan sulphate modifying enzyme), the HLA-C chain of MHCI complex, and the water channel AQP-7. Arginine depletion is a general feature that persists in the more frequently mutated subset, and is complemented by over-representation of mutations to lysine. Arginine to lysine balance is a known factor in determining protein solubility, with higher lysine content being more favourable. Proteins with greater change in arginine to lysine balance are enriched for cell periphery location, where proteostasis is likely to be challenged in tumour cells. Somatic missense mutations in a cancer genome number only in the 10s typically, although can be much higher. Whether the altered arginine to lysine balance is of sufficient scale to play a role in tumour development is unknown.

bioinformatics↗