Integrated Calendar

WASP-Interacting Protein (WIP) is a multifunctional key participant in mediating actin-related cytoskeletal changes in human T cells. WIP is also an intrinsically disordered protein (IDP), lacking any significant secondary or tertiary structure across its 503 residues, and thus defies the ordinarily reliable structure-function paradigm. Our research focuses on how interactions between this ‘hub’ multi-tasker and its various structured binding partners delicately control T cell destiny, in particular the role played by disorder-to-order transitions. Three such critical protein-protein contacts involve the WIP N-terminal domain (with actin), a proline-rich central segment (with cortactin) and the C-terminal domain (with Wiskott-Aldrich syndrome protein, WASP). The first two are of intermediate binding energy (KD ~ 50-3000 nM) and transiently modulate WIP interactions with the actin polymerization machinery. In contrast, the latter forms a tight complex with WASP and inhibits both its activity and eventual degradation in a phosphorylation-dependent manner, explaining why the hereditary Wiskott-Aldrich syndrome immunodeficiency results from WASP mutants unable to bind WIP.
As an IDP, WIP ‘structure’ is essentially an ensemble of multiple conformations contributing to function, and this complexity gives solution NMR – armed with new IDP-optimized methodologies – unrivaled insight into how IDPs exert their biological influence. We established that transient structure in free WIPN and WIPC echoes their bound conformations, uncovering novel binding epitopes in the process. We also observed subtle ensemble shifts induced by environmental factors, such as temperature, denaturant or crowding agents, revealing the biophysics governing WIP behavior in the cellular environment. We further investigated the largest conformational change, experienced by WIPC upon binding to WASP, by determining the contribution of various WIP epitopes to complex affinity, and eventually the structure of the WIP-WASP complex. Finally, we offer an unexpected structural explanation for phosphorylation-induced dissociation of this complex that may explain how this phospho-switch controls WASP degradation. Taken together our results provide a comprehensive map of WIP structure and dynamics and how these affect its interaction with T cell binding partners, and highlight the great impact of high-resolution NMR studies upon the field of biologically active unstructured proteins.

Micro-algae greatly influence present and past oceans. Recently we have come to realize that bacteria interact with micro-algae in various ways, ranging from pathogenicity to mutualism. My research investigates physical and chemical interactions between micro-algae and bacteria across multiple scales; from the chemical crosstalk to the influence these interactions have on the marine environment.
In my talk I will introduce Emiliania huxleyi, the most prevalent micro-alga in modern oceans. I will discuss the role of bacteria as hidden farmers that control the life cycle of algae, determining how fast algae will grow and how fast they will die. I will link laboratory findings to work conducted at sea and demonstrate the importance of these findings in the study of proxies for climate reconstructions.

Proteins generally populate multiple structural states in solution. Transitions between these states are important for function, such as allosteric signaling and enzyme catalysis. Structures solved by X-ray crystallography provide valuable, but static, atomic resolution structural information. In contrast, cross-linking mass spectrometry (XLMS) and small angle X-ray scattering (SAXS) datasets contain information about conformational and compositional states of the system. The challenge lies in the data interpretation since the cross-links in the data often comes from multiple structural states. We have developed a novel computational method that simultaneously uncovers the set of structural states that are consistent with a given dataset (XLMS or SAXS). The input is a single atomic structure, a list of flexible residues, and an experimental dataset. The method finds multi-state models (models that specify two or more co-existing structural states) that are consistent with the data. The method was applied on multiple SAXS and XLMS datasets, including large multi-domain proteins and proteins with long disordered fragments. The applicability of the method extends to other datasets, such as 2D class averages from Electron Microscopy, and residual dipolar couplings.

Range expansions play a crucial role in our evolutionary history and also in human health. Descriptions of stochastic processes similar to Fokker-Planck equations are crucial for understanding the effects of mutations, number fluctuations and selective advantages. Mutations optimally positioned at the front of a growing population can increase their abundance by