RESEARCH THEMES

We aim to understand the molecular mechanisms and signaling pathways that control the distribution and dynamics of subcellular components, focusing on structure, function, molecular mechanism and regulation of the key biomolecular machines and multiprotein complexes that regulate cellular organisation. We also seek to apply that knowledge to develop novel chemical tools to manipulate these systems.

We take a multi-disciplinary approach that combines advanced cell imaging with cell biology, biophysics and structural approaches to define the molecular basis of these dynamic processes.

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LUMENAL CONTENTS OF CYTOPLASMIC MICROTUBULES

Studies over many decades have uncovered the properties of the microtubule polymer and the many motor proteins, microtubule associated proteins, and post-translational modifications, that mostly bind or occur on the exterior surface of the hollow tubule. In contrast, the interior of the microtubule is an extensive expanse of intracellular space about which we know very little. Our data have revealed that F-actin and actin associated protein(s) within this hidden space that we call microtubule lumenal (ML-) actin.

We are aiming to understand its stucture, regulation and function.

MOLECULAR MECHANISMS CONTROLLING THE SPATIAL ORGANISATION OF THE LYSOSOMAL MEMBRANE SYSTEM

It is becoming clear that the spatial organisation of the lysosomal membrane is system is crucial for its metabolic and degradative functions. We are seeking to identify and characterise the proteins and multiprotein complexes that control lysosomal organisation. One key focus is on the structure and function of the FLCN-FNIP complex

SMALL MOLECULES AND PEPTIDES TO TARGET CARGO RECOGNITION AND AUTOREGULATION IN CYTOSKELETAL MOTORS

Following our recent proof-of-concept study, we are seeking to identify and develop new classes of compounds that can manipulate cargo attachment and regulatory mechanisms in the kinesin, dynein and myosin superfamiles. This will allow us to acutely probe the function and regulation of these enzymes and in the future, could serve as the basis for drug development for treatment of disease where motor protein function is dysregulated. We are also exploring how peptide design can be applied discover high-affinity ligands that target kinesin-cargo interactions.

MECHANISITC BASIS FOR CO-OPERATIVITY IN KINESIN-1-CARGO RECOGNITION AND ACTIVATION

The kinesin-1 family of microtubule motors play a central role in many aspects of cell biology and pathology by virtue of their capacity to interact with many different subcellular components known as cargoes. Our work has provided new insights into how kinesin-1 recognises its cargoes and how cargo binding regulates kinesin-1 activity. We are now seeking to understand how co-operative networks of cargo interactions can drive specific functional transport outcomes.