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Publications of the Week

Competitive Organelle-Specific Adaptors Recruit Vps13 to Membrane Contact Sites

By August 1, 2018No Comments

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 This week we profile a recent publication in the Journal of Cell Biology from Dr. Elizabeth Conibear
and Dr. Bjorn Bean (pictured) at the Centre for Molecular Medicine and Therapeutics.

Can you provide a brief overview of your lab’s current research focus?

Each cell has thousands of different types of protein machines. In order to work properly, each protein must be targeted to the correct cellular compartment that both requires its function and provides the right conditions. When transport to these membrane-bound compartments is disrupted proteins cannot carry out their functions effectively and disease can occur. In the Conibear lab, we study the molecular machinery required for this intracellular transport and determine how defects in these pathways result in diseases such as neurodegeneration and cancer. We study this machinery in mammalian cell cultures and, because the machinery is well conserved, in the simpler model organism yeast.

What is the significance of the findings in this publication?

Humans have four VPS13 proteins (VPS13A-D) of unknown function and mutations in each result in a different neurological disorder. In order to better understand the function of VPS13 proteins we turned to yeast, which contains a single Vps13 protein. Yeast Vps13 has previously been observed at several membrane contact sites, regions where cellular compartments are closely tethered allowing the exchange materials between compartments. In this publication, we identify Ypt35 as a novel adaptor that recruits yeast Vps13 to endosomes, vacuoles and a membrane contact site between the vacuole and the endoplasmic reticulum. We then isolate a motif within Ypt35 that mediates this interaction and discover a similar motif in Spo71 and Mcp1, adaptors which recruit Vps13 to the prospore membrane and mitochondria respectively. We show that all adaptors bind to Vps13 at the previously uncharacterized DUF1162 domain and suggest it be renamed the Vps13 Adaptor Binding (VAB) domain. We find that some point mutations in human VPS13B and VPS13D that cause Cohen syndrome and spastic ataxia are in conserved residues of the VAB domain, hinting at functional conservation. Finally, we demonstrate that all Vps13 adaptors compete for Vps13 recruitment providing a mechanism for Vps13 localization under different conditions. Our results offer important insights into how membrane contact site proteins are dynamically recruited and how human VPS13 proteins may have diverged to target different membranes, providing an explanation for the diverse diseases that mutations in human VPS13 proteins can cause.

What are the next steps for this research?

While we have established how Vps13 is targeted to membranes, it is unclear if Vps13 simply acts as a tether, holding membranes together, or if it has other functions. The identification of a common motif in Vps13 adaptors provides a simple way to identify potential further interactors which will help us determine the function of Vps13. Additionally, we are interested in further characterizing the VAB domain to better understand why point mutations in the domain results in human disease. We are working to establish if these mutations cause loss of Vps13 function or localization.

This research was funded by:

This work was supported by funding from Canadian Institutes of Health Research grants 247169 and 365914 and the Canadian Foundation for Innovation (Leading Edge Fund 30636).

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