Department of Structural Dynamics, Max Planck Institute for Biophysical Chemistry, Georg-August-University of Göttingen, Göttingen, Germany
"GTPases are ubiquitous regulators of cell signaling which cycle between their active GTP-bound and inactive GDP-bound forms. Among translational GTPases, elongation factor G (EF‑G) stands out, because it generates force to promote the movement of the ribosome along the mRNA at the cost of GTP hydrolysis. The key unresolved question is how GTP hydrolysis drives forward tRNA movement. In our study we visualize the GTPase-powered step of ongoing translocation using time-resolved cryo-electron microscopy (cryo-EM). In the EF-G–GDP–Pi state captured on the ribosome prior to translocation, the GTPase switch 1 (sw1) region forms a compact bridge between the small and large ribosomal subunits (SSU and LSU), inducing subunit rotation and twisting of the sarcin-ricin loop (SRL) of the LSU. Remodeling of sw1 upon Pi release loosens the SSU contacts, which triggers a large-scale rigid body rotation of EF-G pivoting at the SRL. The global motion of EF-G relative to the ribosome exerts force to pry apart the SSU head and body domains, resulting in forward movement of the tRNAs on the SSU. The findings demonstrate how an unconventional GTPase cycle synchronizes spontaneous thermal fluctuations of the ribosome into force-generating molecular movement."
Valentyn Petrychenko was born in Ukraine in a small town called Dubno in the west part of the country. He did his Bachelor's studies in the Taras Shevchenko National University of Kyiv, where he started as a General Biologist and further specialized in Molecular Biology. He did his diploma project at the Institute for Molecular Biology and Genetics of the National Academy of Science of Ukraine investigating Tyr-aaRS complexes using MD simulations. He was awarded IMPRS Stipend for Molecular Biology MSc/PhD program at the Georg-August University of Göttingen. He did his Master’s diploma project studying cryo-electron microscopy at Max Planck Institute for biophysical chemistry in the department of Structural dynamics. There he continued further with PhD project studying protein translation using high-resolution Cryo-EM.
Structural Studies Division, MRC Laboratory of Molecular Biology, University of Cambridge, Cambrdige, United Kingdom
"G protein-coupled receptors (GPCRs) are membrane proteins that are implicated in a wide range of physiological functions and are targets for one-third of all commercial drugs. GPCRs are divided phylogenetically into six classes, A-F. Over 400 structures of monomeric GPCRs have been determined and their mechanism of activation and coupling to a G protein has been well studied. However, with the exception of Class C GPCRs that exist as obligate dimers due to the extracellular Venus flytrap domains, how canonical GPCRs that lack such domains form and function as dimers has been poorly characterized. I will present five cryo-EM structures of Ste2 captured in multiple states along its entire activation pathway. These structures reveal a new activation mechanism that is different from all other GPCRs studied thus far. Notably, the Ste2 dimer has evolved a different mechanism to configure the movement of transmembrane helices 6 and 7 upon agonist binding to allow G protein coupling and provides the first model for how interactions at the dimer interface can alter during receptor activation, which could have implications for understanding signalling in other GPCR dimers. Furthermore, the structures provide a template for the design of novel drugs against the widely conserved fungal GPCRs, which could be exploited for the treatment of several intractable fungal diseases."
Vaithish Velazhahan is currently a third year PhD student and a Gates Cambridge Scholar in the group of Dr. Chris Tate, FRS, at the MRC Laboratory of Molecular Biology (MRC LMB) and the University of Cambridge. Vaithish graduated with honors bachelors degrees in Medical Biochemistry and Microbiology from Kansas State University where he used biophysical techniques and NMR to study molecular interactions of dietary flavonoids with regulatory proteins implicated in cancer. He then started his PhD where he develops techniques and uses cryo-EM to understand the molecular details of GPCR (G protein-coupled receptors) dimerisation, which are major physiological targets for drug development.
Department of Molecular Genetics, Weizmann Institute of Science, Rechovot, Israel
"Nascent mRNA is endowed with a poly(A) tail, which is subject to gradual deadenylation in the cytoplasm, followed by mRNA degradation. Deadenylation and degradation rates are typically correlated, rendering it difficult to dissect the individual determinants governing each of these processes. In this study we developed an approach allowing systematic, robust and multiplexed quantification of poly(A) tails. Our results suggest that in yeast, exclusively during meiosis, mRNA deadenylation and degradation rates are decoupled. The decoupled regime in meiosis allowed us to discover transcript length as a major determinant of deadenylation rates and as a key contributor to the reshaping of poly(A) tail lengths in meiosis. Our study highlights a novel determinant of mRNA deadenylation, and demonstrates how decoupling of deadenylation from degradation can lead to reshaping of poly(A) tail profiles and gene expression over the course of a biological response."
David Wiener is a 4th year PhD student at the Weizmann Institute of Science. During his first degree at the Pontificia Universidad Católica de Chile, he studied the subcellular localization of BRCA1 in breast cancer tumors. Amazed by the complexity of biological systems, he realized that computational skills are required to understand them quantitatively. His PhD research focuses on understanding one of the most intriguing features of mRNAs, the poly(A) tail. For this, he combines mathematical modeling, high-throughput experimental protocols, and the development of tailored computational pipelines to characterize factors that shape the poly(A) tail length and understand how they impact gene expression. For his future research steps, I am interested in applying the skills acquired in his PhD to understand the gene expression control mechanisms that shape marine microbial communities.