Abstract
Autophagy is a key clearance process to recycle damaged cellular components. One important upstream regulator of autophagy is ULK1 kinase. Several three-dimensional structures of the ULK1 catalytic domain are available, but a comprehensive study, including molecular dynamics, is missing. Also, an exhaustive description of ULK1 alterations found in cancer samples is presently lacking. We here applied a framework which links -omics data to structural protein ensembles to study ULK1 alterations from genomics data available for more than 30 cancer types. We predicted the effects of mutations on ULK1 function and structural stability, accounting for protein dynamics, and the different layers of changes that a mutation can induce in a protein at the functional and structural level. ULK1 is down-regulated in gynecological tumors. In other cancer types, ULK2 could compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression have been found. 36 missense mutations of ULK1, not limited to the catalytic domain, are co-occurring with mutations in a large number of ULK1 interactors or substrates, suggesting a pronounced effect of the upstream steps of autophagy in many cancer types. Moreover, our results pinpoint that more than 50% of the mutations in the kinase domain of ULK1, here investigated, are predicted to affect protein stability. Three mutations (S184F, D102N, and A28V) are predicted with only impact on kinase activity, either modifying the functional dynamics or the capability to exert effects from distal sites to the functional and catalytic regions. The framework here applied could be extended to other protein targets to aid the classification of missense mutations from cancer genomics studies, as well as to prioritize variants for experimental validation, or to select the appropriate biological readouts for experiments.
Highlights
Autophagy is a key clearance process to recycle damaged cellular components
We focus on the effects of mutations found in cancer samples in ULK1 kinase domain, since it is the only region with an available experimental structure
The assessment of the different effects that a mutation can exert on a protein explored in this study and the subsequent classification of the mutations can provide a useful complement to cancer genomics studies
Summary
Autophagy is a key clearance process to recycle damaged cellular components. One important upstream regulator of autophagy is ULK1 kinase. We here applied a framework which links -omics data to structural protein ensembles to study ULK1 alterations from genomics data available for more than 30 cancer types. We predicted the effects of mutations on ULK1 function and structural stability, accounting for protein dynamics, and the different layers of changes that a mutation can induce in a protein at the functional and structural level. The ULK1 (Unc-51 like autophagy activating kinase 1) complex initiates a utophagy[6,7,8]. In most of the cases, autophagy initiation is regulated by the interplay between mTOR (mammalian Target of Rapamycin) and AMPK (AMP-activated protein kinase) complexes. X-ray structures of ULK1 in complex with inhibitors are available (PDB entries: 4 WNO31, 4WNP31, 5CI732, 6QAS34, and 6MNH35)
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