Basic Life Science Research Associate, Biology
Bachelor of Science, Nankai University (2007)
Master of Science, Nankai University (2010)
Doctor of Philosophy, University of California Riverside (2015)
Or Gozani, Postdoctoral Faculty Sponsor
Chemical linguistics: Reading the modified proteome.
2021; 81 (12): 2501-2503
In this issue of Molecular Cell, Lin etal. (2021) develop a tri-functional amino acid probe for the discovery and characterization of protein domains that sense or "read" protein post-translational modifications, a chemical tool that can facilitate our understanding of how signaling networks act at the molecular level.
View details for DOI 10.1016/j.molcel.2021.05.011
View details for PubMedID 34143967
METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.
Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis invivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity invitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs thattarget growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.
View details for PubMedID 30612740
SETD3 is an actin histidine methyltransferase that prevents primary dystocia.
For more than 50 years, the methylation of mammalian actin at histidine 73 has been known to occur1. Despite the pervasiveness of His73 methylation, which we find is conserved in several model animals and plants, its function remains unclear and the enzyme that generates this modification is unknown. Here we identify SET domain protein 3 (SETD3) as the physiological actin His73 methyltransferase. Structural studies reveal that an extensive network of interactions clamps the actin peptide onto the surface of SETD3 to orient His73 correctly within the catalytic pocket and to facilitate methyl transfer. His73 methylation reduces the nucleotide-exchange rate on actin monomers and modestly accelerates the assembly of actin filaments. Mice that lack SETD3 show complete loss of actin His73 methylation in several tissues, and quantitative proteomics analysis shows that actin His73 methylation is the only detectable physiological substrate of SETD3. SETD3-deficient female mice have severely decreased litter sizes owing to primary maternal dystocia that is refractory to ecbolic induction agents. Furthermore, depletion of SETD3 impairs signal-induced contraction in primary human uterine smooth muscle cells. Together, our results identify a mammalian histidine methyltransferase and uncover a pivotal role for SETD3 and actin His73 methylation in the regulation of smooth muscle contractility. Our data also support the broader hypothesis that protein histidine methylation acts as a common regulatory mechanism.
View details for PubMedID 30626964