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Cambridge Institute for Medical Research


Characterising the secretory pathway machinery 

General audience summary:
Cells are internally compartmentalised. This allow proteins and lipids that participate in the same biochemical pathways to have higher local concentrations, and proteins that could potentially damage other cellular components (eg. protein degrading enzymes called proteases) to be segregated from other cellular components.

Establishing and maintaining this sub-cellular organisation is a complex task that requires sophisticated machinery to allow proteins to be delivered to the correct place in the cell, without mis-delivering other proteins.

Defects in these sorting pathways result in protein accumulation or mislocalisation, and is one of the major causal factors for neurodegenerative disorders such as Parkinson's or Alzheimer's diseases.

Our group is focussed on trying to understand the fundamental cell biology that allows the cell to sort proteins to the correct subcellular compartments.

Strategic CIMR themes: Membrane Trafficking, Organelle Biology, Rare Genetic Diseases

Funding: Wellcome Trust, Royal Society

Research Group Members: Jessica Eden, Eleanor Fox, Marie Pereira, Daniele Stalder, Georgia Miller


Characterising the secretory pathway machinery

Defects in protein trafficking are a causal factor of incurable, neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases. Despite the great efforts made in the last 20 years to study intracellular protein trafficking, there are still gaps in our understanding of these pathways. Understanding the complexity of protein sorting pathways is critical for the potential future development of new therapies. 

One example of a poorly understood trafficking pathway is the secretory route from the Golgi apparatus to the plasma membrane. The secretory route from the Golgi, represents a major transport route of transmembrane proteins and soluble proteins from their site of synthesis in the ER. This secretory route also has an important role in human diseases as cytokines, lipoproteins and antibodies are all secreted in this manner.

In previous work ( we have been able to reproducibly visualise tubules that bud from the Golgi apparatus with a high spatio-temporal resolution. 

Our lab is using this strategy and others to understand the secretory machinery in more detail. This will be accomplished by investigating and probing the kinetics of the known secretory components and by identifying new proteins and lipids that form and traffic in Golgi tubules.

To achieve these goals the lab uses a number of different and complementary approaches including confocal microscopy, super-resolution microscopy, biochemistry, proteomics and lipidomics.


Key publications: 

Yu Chen,* David C. Gershlick,* Sang Yoon Park,* and Juan S. Bonifacino, Journal of Cell Biology (2017)

Maria Lucas*, David C. Gershlick*, Ander Vidaurrazaga, Adriana L. Rojas, Juan S. Bonifacino, Airtor Hierro,  Structural Mechanism for Cargo Recognition by the Retromer Complex, Cell, (2016)

David C. Gershlick, Christina Schindler, Yu Chen, and Juan S. Bonifacino, TSSC1 is novel component of the endosomal retrieval machinery Molecular Biology of the Cell, (2016)

David C. Gershlick, Carine de Marcos Lousa, Ombretta Foresti, Andrew J. Lee, Estela A. Pereira, Luis L.P. daSilva, Francesca Bottanelli and Jurgen Denecke, Golgi-Dependent Transport of Vacuolar Sorting Receptors Is Regulated by COPII, AP1, and AP4 Protein Complexes in Tobacco, The Plant Cell, (2014)

Sir Henry Dale Fellow

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