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    PublicationOpen Access
    Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras
    (Elsevier, 2020) Vatansever, Sezen; Gümüş, Zeynep H.; Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997
    K-Ras is the most frequently mutated protein in human cancers. However, until very recently, its oncogenic mutants were viewed as undruggable. To develop inhibitors that directly target oncogenic K-Ras mutants, we need to understand both their mutant-specific and pan-mutant dynamics and conformations. Recently, we have investigated how the most frequently observed K-Ras mutation in cancer patients, G12D, changes its local dynamics and conformations (Vatansever et al., 2019). Here, we extend our analysis to study and compare the local effects of other frequently observed oncogenic mutations, G12C, G12V, G13D and Q61H. For this purpose, we have performed Molecular Dynamics (MD) simulations of each mutant when active (GTP-bound) and inactive (GDP-bound), analyzed their trajectories, and compared how each mutant changes local residue conformations, inter-protein distance distributions, local flexibility and residue pair correlated motions. Our results reveal that in the four active oncogenic mutants we have studied, the α2 helix moves closer to the C-terminal of the α3 helix. However, P-loop mutations cause α3 helix to move away from Loop7, and only G12 mutations change the local conformational state populations of the protein. Furthermore, the motions of coupled residues are mutant-specific: G12 mutations lead to new negative correlations between residue motions, while Q61H destroys them. Overall, our findings on the local conformational states and protein dynamics of oncogenic K-Ras mutants can provide insights for both mutant-selective and pan-mutant targeted inhibition efforts.
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    Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
    (Nature Research, 2021) Muus, Christoph; Luecken, Malte D.; Eraslan, Gökcen; Sikkema, Lisa; Waghray, Avinash; Heimberg, Graham; Kobayashi, Yoshihiko; Vaishnav, Eeshit Dhaval; Subramanian, Ayshwarya; Smillie, Christopher; Jagadeesh, Karthik A.; Duong, Elizabeth Thu; Fiskin, Evgenij; Triglia, Elena Torlai; Ansari, Meshal; Cai, Peiwen; Lin, Brian; Buchanan, Justin; Chen, Sijia; Shu, Jian; Haber, Adam L.; Chung, Hattie; Montoro, Daniel T.; Adams, Taylor; Aliee, Hananeh; Allon, Samuel J.; Andrusivova, Zaneta; Angelidis, Ilias; Ashenberg, Orr; Bassler, Kevin; Bécavin, Christophe; Benhar, Inbal; Bergenstråhle, Joseph; Bergenstråhle, Ludvig; Bolt, Liam; Braun, Emelie; Bui, Linh T.; Callori, Steven; Chaffin, Mark; Chichelnitskiy, Evgeny; Chiou, Joshua; Conlon, Thomas M.; Cuoco, Michael S.; Cuomo, Anna S. E; Deprez, Marie; Duclos, Grant; Fine, Denise; Fischer, David S.; Ghazanfar, Shila; Madissoon, Elo; Nyquist, Sarah K.; Penland, Lolita; Shi, Xingyi; Sountoulidis, Alex; Travaglini, Kyle J.; Huyck, Heidie L.; N/A; Yıldırım, Ali Önder; Other; School of Medicine; N/A
    Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial–macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.