September 17, 2024 at 12:15

SBBS introductory meeting for students 

ZOOM

If you missed the introduction meeting, feel free to contact one of the organisers by email or at the first seminar.

October 8, 2024 at 12:15, room U1.197

Title: Seeing Amyloid: Beautiful Structures and Toxic Mechanisms

Many amyloid precursors are intrinsically disordered initially, yet fold to highly organised cross-beta structures during amyloid formation. How this conformational transition occurs structurally is not clear, with the initiating steps in aggregation being difficult to study because of the dynamics and heterogeneity of the species involved. It is also clear that the energy landscape for aggregation into amyloid resulting in potentially many different amyloid folds. In this presentation I will discuss these concepts, drawing on recent results from our laboratory on the amyloidogenic proteins islet associated polypeptide (IAPP) involved in type 2 diabetes and A-beta in Alzheimer’s disease. I will show how by combining kinetic analysis of amyloid assembly with structural analysis of fibril assembly in vitro and in situ we are beginning to link the pathway of structural conversion from the initial unfolded monomer to the cross-beta amyloid fold. The insights are fuelling our quest to better understand the link between the structures of amyloid assemblies and the onset of disease.

Prof. Sheena Radford 
University of Leeds - United Kingdom

October 15, 2024 at 12:15, room U1.197

Title: Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids 

Abnormal assembly of tau, α-synuclein, TDP-43 and amyloid-β proteins into amyloid filaments defines most human neurodegenerative diseases. Genetics provides a direct link between filament formation and the causes of disease. Developments in cryo-electron microscopy (cryo-EM) have made it possible to determine the atomic structures of amyloids from postmortem human brains. I will briefly review the structures of brain-derived amyloid filaments that have been determined so far and then discuss their impact on research into neurodegeneration. Whereas a given protein can adopt many different filament structures, specific amyloid folds define distinct diseases. Amyloid structures thus provide a description of neuropathology at the atomic level and a basis for studying disease. Future research should focus on model systems that replicate the structures observed in disease to better understand the molecular mechanisms of disease and develop improved diagnostics and therapies. 

Sjors Scheres
MRC Laboratory of Molecular Biology Cambridge - United Kingdom 

TBA, 2024 at 12:15, room U1.197

Title: TBA

TBA

TBA

November 19, 2024 at 12:15, room U1.197

Title: Memory and directionality in the protein dynamics of Hsp90

The homodimeric molecular chaperone and heat shock protein Hsp90 is a member of the GHKL superfamily (Gyrase, Hsp90, Histidine Kinase, MutL) whose members share structural

similarities, especially in the ATP-binding domain. Hsp90 is an energy-consuming machine, that dynamically interacts with several cochaperones and client proteins while undergoing large conformational changes. During the last years, the structure of some of these multi-protein complexes, their affinities and the time scales of conformational changes have been determined. Less clear are the dynamics of complex formation, how local perturbations can lead to global conformational changes and for which time perturbations affect a protein’s dynamic structure.

Here I will address these questions and show how a combination of single-molecule fluorescence, quasi-elastic neutron scattering and MD simulations on Hsp90 can best be explained by molecule-spanning dynamics on the nanosecond time scale. This challenges the prevailing picture, in which slow protein dynamics (microsecond to minute time scale) are associated with large conformational changes, whereas nano- and picosecond dynamics are linked to local motions, e.g. side chain movements. 

Then I will show that Hsp90 can potentially remember a conformational state for around one minute, although the transition rates are on the timescale of seconds. Finally, I will demonstrate how multi-protein interactions and ATP-hydrolysis can lead to a functional Hsp90-chaperone-client cycles, which efficiently uses cellular energy resources for kinase maturation.

Prof. Thorsten Hugel
University of Freiburg - Germany

December 3, 2024 at 12:15, room U1.197 - CANCELLED

Title: Exploring the molecular architecture of native actin assemblies using cryo-electron tomography

Actin contributes to an extraordinary range of cellular processes by assembling and disassembling highly dynamic and ordered structures. At the structural level, little is known about how the molecular players of the actin machinery work together inside cells to produce force-generating actin systems. In recent years, cryo-electron tomography (cryo-ET) has become the method of choice for structural analysis of the cell interior at the molecular level. In this talk, I will give a tour of our past and present cryo-ET work on different cellular actin structures and show how they have begun to open new avenues for understanding actin assembly in situ at the actin cytoskeleton-membrane interface.

Dr. Marion Jasnin
Helmholtz Munich - Germany

December 10, 2024 at 12:15, room U1.197

Title: Protein dynamics and mechanics at the single-molecule level

It is well recognized that the internal dynamics of proteins is central to understanding cellular functions. This concept is evident for instance during protein folding, where dynamic misfolding events can trigger aggregation and cellular malfunction. Revealing these processes is highly challenging, even as structural and biochemical methods are increasingly addressing conformational changes. I will discuss how my group is using single-molecule optical tweezers methods for this purpose. We have previously studied how diverse chaperones assist in the folding of proteins away from the ribosome. In this talk, I will focus on recent efforts to understand the conformational dynamics of nascent chains that emerge from ribosomes. We are interested in how the nascent chains of adjacent ribosomes interact, and how chaperones bind nascent chains, during the process of translation. Here, we combined our single-molecule tools with ribosome profiling, which together revealed several surprises, ranging from ubiquitous co-translational dimerization to the surprising mathematical predictability of trigger factor and DnaK throughout the proteome. If time allows, I will discuss recent efforts to study Cdc48 mediated processing of polyubiquitin.

Prof. Sander Tans
AMOLF/ Delft University of Technology - Netherlands