InstructThe latest webinar in the Instruct-ERIC Structure Meets Function series is hosted by Instruct-FI. The webinar series offers an insight into the very cutting edge of structural biology research, utilising the latest techniques available through Instruct-ERIC facilities and centres.
This month is no different, with three speakers who have accessed technologies across the Finland centre. Instruct-FI is made up of the University of Helsinki, the University of Oulu, and the University of Eastern Finland. Visit the centre page to find out more about the facilities, and technologies available at each institution.
The webinar takes place 11:00 CET (10:00 BST, 12:00 EEST), on 17 October.
Take a look at the previous webinars in the series here.
The full speaker list and their talk titles will be available soon.
Chair: Janne Janis - University of Eastern Finland
Speaker 1: Ilona Rissanen - University of Helsinki
Title: Structure meets potency: Insights into effective SARS-CoV-2 inhibition
Abstract: The emergence of increasingly immunoevasive SARS-CoV-2 variants emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Intranasal administration of neutralizing antibodies has shown encouraging protective potential but there remains a need for SARS-CoV-2 blocking agents that are less vulnerable to mutational viral variation and more economical to produce in large scale. Here we describe TriSb92, a highly manufacturable and stable trimeric antibody-mimetic sherpabody targeted against a conserved region of the viral spike glycoprotein. TriSb92 potently neutralizes SARS-CoV-2, including the latest Omicron variants like BF.7, XBB, and BQ.1.1. In female Balb/c mice intranasal administration of just 5 or 50 micrograms of TriSb92 as early as 8 h before but also 4 h after SARS-CoV-2 challenge can protect from infection. Cryo-EM and biochemical studies reveal triggering of a conformational shift in the spike trimer as the inhibitory mechanism of TriSb92. The potency and robust biochemical properties of TriSb92 together with its resistance against viral sequence evolution suggest that TriSb92 could be useful as a nasal spray for protecting susceptible individuals from SARS-CoV-2 infection.
Speaker 2: Giovanna Viola - University of Verona
Title: Investigating the influence of ubiquitination on the conformational propensities of the amyloidogenic Tau protein by mass spectrometry methods
Abstract: The microtubule associated protein Tau is a n intrinsically disordered protein (abundant in neuronal axons where it promotes and stabilizes the microtubule assembly. In pathological conditions, such as in Alzheimer’s disease (AD), post translational modifications (PTMs) are greatly implicated in aberrant accumulation of Tau. Mounting evidence suggest that hyperphosphorylation facilitates the self assembly of Tau into paired helical filaments (PHFs) that accumulate as fibrillary tangles. This results in the loss of axonal or dendritic transport as well as disassembly of the microtubules. Besides phosphorylation, ubiquitination, in combination with other PTMs, is thought to play a role in modulating Tau aggregation. Assessing how PTMs remodel the protein conformational landscape will pave the way for developing strategies aimed at mitigating aberrant structural transformations, offering opportunities in chemical biology and molecular therapeutics. With this project, we strive to detect key conformational transitions that precede irreversible protein accumulation and to establish structure-(mis)function relationships for selected proteoforms. We apply native mass spectrometry (nMS) and ion mobility mass spectrometry (IM MS), which have emerged as informative methods to study intrinsically disordered proteins. Through its soft ionization process, electro spray ionization (ESI) generally does not involve molecules fragmentation and noncovalent interactions can be preserved enabling to retain the ‘native’ state of the compounds. ESI MS can provide information on the conformational heterogeneity and compaction of flexible proteins. Mass spectra acquire d under native conditions, show a typical profile for folded and unfolded proteins, due the different ‘compactness’ against solvent polarization. The Ion Mobility (IM) technique adds an extra dimension by separating protein ions on the basis of their overall size. The experiment yields arrival time distributions which can be converted to distributions of rotationally averaged collisional cross sec tions (CCSs). nMS and IM MS measurements will be used to assay the intrinsic conformational landscape of differently ubiquitinated Tau proteoforms and their changes from monomeric to early aggregation states Samples of mono and di-mono-ubiquitinated Tau species are produced via chemoselective disulfide coupling which allows to install ubiquitin at the desired position, a crucial aspect to derive proteoform specific behavior.
