BEGIN:VCALENDAR VERSION:2.0 PRODID:icalendar-ruby CALSCALE:GREGORIAN METHOD:PUBLISH BEGIN:VTIMEZONE TZID:Europe/Vienna BEGIN:DAYLIGHT DTSTART:20240331T030000 TZOFFSETFROM:+0100 TZOFFSETTO:+0200 RRULE:FREQ=YEARLY;BYDAY=-1SU;BYMONTH=3 TZNAME:CEST END:DAYLIGHT BEGIN:STANDARD DTSTART:20231029T020000 TZOFFSETFROM:+0200 TZOFFSETTO:+0100 RRULE:FREQ=YEARLY;BYDAY=-1SU;BYMONTH=10 TZNAME:CET END:STANDARD END:VTIMEZONE BEGIN:VEVENT DTSTAMP:20260424T143500Z UID:1701077400@ist.ac.at DTSTART:20231127T103000 DTEND:20231127T113000 DESCRIPTION:Speaker: Leoni Abendstein\nhosted by Martin Loose\nAbstract: In our research\, we focused on understanding the activation of the classica l complement pathway and the unique features of IgG3 antibodies. The class ical complement pathway is initiated by antigen-bound IgG antibodies\, whi ch oligomerize to activate complement through the hexameric C1q complex. S urprisingly\, structural data has revealed that it is not essential to eng age all six arms of C1q to initiate complement activation. This highlights a symmetry mismatch between C1 and the hexameric IgG complex\, which rema ins unexplained.To address these questions\, we use DNA nanotechnology to engineer specific nanostructures for antigen templating\, allowing us to c ontrol the valency of IgG. These DNA nano-templated IgG complexes were abl e to activate complement on cell-mimetic lipid membranes\, offering valuab le insights into the impact of IgG valency on complement activation withou t the need to mutate the antibodies. We employed biophysical assays in con junction with 3D cryo-electron tomography to investigate this phenomenon f urther. Our findings show that the cleavage of complement component C4 by the C1 complex is proportional to the number of antigens present. Addition ally\, higher IgG valency correlated with improved activation of the termi nal complement pathway and the formation of the membrane attack complex. T hese results demonstrate how nanopatterning antigen-antibody complexes inf luence C1 complex activation\, suggesting potential routes for modulating complement activation through antibody engineering.In a parallel line of r esearch\, we explored the unique characteristics of IgG3 antibodies. IgG3 stands out among IgG subclasses due to its extended hinge region\, allotyp ic diversity\, and superior effector functions\, such as highly efficient pathogen neutralization and complement activation. Despite its potential\, IgG3 has been underrepresented as an immunotherapeutic candidate\, primar ily due to a lack of structural information. To bridge this knowledge gap\ , we use cryoEM to determine the structures of antigen-bound IgG3\, both i n isolation and in complex with complement components. These structural an alyses unveiled a tendency for IgG3-Fab clustering\, facilitated by the fl exible upper hinge region specific to IgG3\, potentially maximizing pathog en neutralization through high-density antibody arrays. IgG3 also forms el evated hexameric Fc platforms that extend above the protein corona\, enhan cing receptor binding and interactions with the complement C1 complex\, wh ich displayed a unique protease conformation in this context\, possibly pr eceding C1 activation. Mass spectrometry results indicated that C1 deposit s C4b directly onto specific IgG3 residues in proximity to the Fab domains . This is attributed to the height of the C1-IgG3 complex. This knowledge is valuable for the development and design of future immunotherapeutics ba sed on IgG3\, potentially expanding its role in therapeutic applications. LOCATION:Sunstone Building - Big Seminar Room B \, ISTA ORGANIZER: SUMMARY:Leoni Abendstein: Structural insights into the activation of the cl assical complement system URL:https://talks-calendar.ista.ac.at/events/4588 END:VEVENT END:VCALENDAR