Onea, G. | bioRxiv Science

bioRxiv2024

Data- and knowledge-derived functional landscape of human solute carriers

Research on the understudied solute carrier (SLC) superfamily of membrane transporters would greatly profit from a comprehensive knowledgebase, synthesizing data and knowledge on different aspects of SLC function. We consolidated multi-omics data sets with selected curated information from the public domain, such as structure prediction, substrate annotation, disease association and subcellular localization. This SLC-centric knowledge is made accessible to the scientific community via a web portal, featuring interactive dashboards and a tool for family-wide, tree-based visualization of SLC properties. Making use of the systematically collected and curated data sets, we selected eight feature-dimensions to compute an integrated functional landscape of human SLCs. This landscape represents various functional aspects, harmonizing local and global features of the underlying data sets, as demonstrated by inspecting structural folds and subcellular locations of selected transporters. Based on all available data sets and their integration, we assigned a biochemical/biological function to each SLC, making it one of the largest systematic annotations of human gene function and likely acting as a blueprint for future endeavours.

systems biology↗

bioRxiv2024

Interplay between β-propeller subunits WDR26 and muskelin regulates the CTLH E3 ligase supramolecular complex

The Pro/N-degron recognizing C-terminal to LisH (CTLH) complex is an E3 ligase of emerging interest in the developmental field and for targeted protein degradation (TPD) modalities. The human CTLH complex forms distinct supramolecular ring-shaped structures dependent on the multimerization of WDR26 or muskelin {beta}-propeller proteins. Here, we find that, in human cells, CTLH complex E3 ligase activity is dictated by a dynamic exchange between WDR26 and muskelin in tandem with muskelin autoregulation. Proteomic experiments revealed that complex-associated muskelin protein turnover is a major ubiquitin-mediated degradation event dependent on the CTLH complex in unstimulated HeLa cells. We observed that muskelin and WDR26 binding to the scaffold of the complex is interchangeable, indicative of the formation of separate WDR26 and muskelin complexes, which correlated with distinct proteomes in WDR26 and muskelin knockout cells. We found that mTOR inhibition-induced degradation of Pro/N-degron containing protein HMGCS1 is distinctly regulated by a muskelin-specific CTLH complex. Finally, we found that mTOR inhibition also activated muskelin degradation, likely as an autoregulatory feedback mechanism to regulate CTLH complex activity. Thus, rather than swapping substrate receptors, the CTLH E3 ligase complex controls substrate selectivity and its autoregulation through exchanging its {beta}-propeller oligomeric subunits WDR26 and muskelin.

molecular biology↗