February 27, 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.

March 19, 2024 at 12:15, room U1.197

Title: Conformational ensembles of the human intrinsically disordered proteome

Intrinsically disordered proteins and regions (collectively IDRs) are pervasive across proteomes in all kingdoms of life, help shape biological functions, and are involved in numerous diseases. IDRs populate a diverse set of transiently formed structures yet defy commonly held sequence-structure-function relationships. Recent developments in protein structure prediction have led to the ability to predict the three-dimensional structures of folded proteins at the proteome scale and have enabled large-scale studies of structure-function relationships. In contrast, knowledge of the conformational properties of IDRs is scarce, in part because the sequences of disordered proteins are poorly conserved and because only few have been characterized experimentally. In my talk I will describe how we can use molecular simulations with coarse- grained models to study the relationship between sequence, conformational properties, and functions of IDRs.

First, I will describe how we have used experimental data on more than 50 different proteins to learn a coarse-grained molecular energy function to predict conformational properties of IDPs. By globally optimizing a transferable model, called CALVADOS, we can study the conformational ensemble of an IDP in the absence of experimental data. I will describe the Bayesian formalism we developed to parameterize CALVADOS by targeting experimental data on IDRs. I will briefly describe how this model enables us to study interactions within and between IDRs in biomolecular condensates.

Second, I will describe how CALVADOS makes it possible to perform large-scale simulations to explore the relationship between sequence, structure, and function of IDRs. I will describe how we have generated conformational ensembles of all intrinsically disordered regions of the human proteome, and used these to provide insight into sequence-ensemble relationships and evolutionary conservation of IDR properties.

Finally, I will describe initial work on how we can use the information encoded in CALVADOS to design disordered proteins with desired conformational properties. I will describe the basic design algorithm and experimental validation on both single-chain compaction and measurements of phase separation.

Prof. Kresten Lindorff-Larsen 
University of Copenhagen - Denmark

March 26, 2023 at 12:15, room U1.197

Title: Structural basis for bacterial protein disaggregation and proteolysis 

Protein homeostasis is meticulously maintained across all cells, spanning from archaea to humans. Any deviation from the equilibrium of the proteome, induced by stress or cellular aging, leads to the accumulation of misfolded proteins, contributing to cellular toxicity. A complex proteostasis network actively manages misfolded proteins through processes such as refolding, degradation, or sequestration into intracellular inclusions. Integral to this protein quality control system are ATPases from the AAA+ superfamily (ATPases Associated to a variety of cellular Activities).

These AAA+ proteins, universally present in organisms, share a common structural fold for ATP hydrolysis, but each possesses distinct function-specific domains, enabling specialization in particular cellular activities and interactions with regulatory protein partners.

Our work focuses on the structural investigation of bacterial Hsp100 AAA+ chaperones involved in protein quality control. We aim at understanding their fine-tuned regulation, which is absolutely required by the bacterium to survive harsh environment conditions and useful for us in the effort of killing pathogenic bacterial strains. Using cryo-EM in combination with biochemical functional assays, we can describe the molecular tuning mechanisms used by bacteria to assure the disaggregation or proteolysis of toxic protein species only, while leaving intact functional protein molecules. 
 

Marta Carroni
Stockholm University - Sweden

April 2, 2024 at 12:15, room U1.197

Title: Time-resolved serial crystallography studies of conformational changes in cytochrome c oxidase

Time-resolved X-ray crystallography allows time-dependent structural changes to be visualized as they evolve within protein crystals and can yield unique structural insights into the course of a biochemical reaction. Serial crystallography is now routinely used for time-resolved X-ray diffraction studies of macromolecules at X-ray free electron laser and synchrotron radiation facilities. As the field grows, biological reactions that are not naturally light sensitive will be increasingly studied using time-resolved serial crystallography. In this work, a laser-flash was used to release photocaged oxygen and thereby initiate the reduction of oxygen to water in microcrystals of cytochrome c oxidase. Our structural results suggest how this reaction may be coupled to gating the uptake of protons from the cytoplasm and to the release of protons to the periplasm. Similar interdisciplinary experiments will allow other biological reactions to become accessible to time-resolved diffraction.

Prof. Richard Neutze
University of Gothenburg - Sweden

April 16, 2024 at 12:15, room U1.197

Title: Double trouble—regulation of ubiquitination by pseudokinases and substrate adaptors

The Tribbles family of pseudokinases (TRIB1–3) recruit substrates to the COP1 ubiquitin ligase for ubiquitin-mediated protein degradation. In humans, COP1 complexes ubiquitinate transcription factors that control differentiation of metabolic and immune cells, and substrates are particularly relevant in metabolic disease and acute myeloid leukaemia. Moreover, COP1 co-operates with the DET1-DDB1-DDA1 (DDD) complex, which acts as a substrate adaptor for Cullin based ubiquitin ligation. Using a combination of crystallography, cryo-EM, Alphafold modelling and biochemistry we are characterising the functional architecture of Tribbles-COP1-DET1 ligase complexes. In this seminar I will discuss our current working model for complex assembly, and execution of ubiquitination. I will also describe the potential for small molecule agents and nanobody tools to specifically trap Tribbles proteins to affect complex function. More fundamentally, I will discuss the requirement for such a complex multilayered arrangement of substrate adaptors and ligase enzymes to regulate transcription factor degradation.

Prof. Peter Mace
University of Otago - New Zealand

TBA

May 28, 2024 at 12:15, room U1.197

Title: TBA

Dr. Theodoros Karamanos
Imperial College London - United Kingdom