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 This week we profile a recent publication in Autophagy from the laboratory of
Dr. Calvin Yip (left, pictured with lab) at the UBC Life Sciences Institute.

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

Autophagy is an evolutionarily conserved pathway that encapsulates objects to be degraded in a double-membrane vesicle called the autophagosome and targeting this cargo to the lysosome for breakdown. Defects in this pathway have been implicated in neurodegenerative disorders, cancers, and other human diseases. The significance of the autophagy was highlighted by the awarding of the 2016 Nobel Prize in Medicine to Dr. Yoshinori Ohsumi for his pioneering effort in molecular dissection of this pathway. The overall interest of our lab is to understand how at the molecular level the core protein machineries of autophagy mediates the different steps of this important membrane trafficking and degradative pathway. For the past few years, we have been using an approach combining structural biology, biochemistry, and cell biology to characterize a protein complex known as the Atg1/ULK complex which is multi-protein signalling complex that serves as a major “on/off” switch of the autophagy.

What is the significance of the findings in this publication?

Much of the published studies have focused on the Atg1 complex from budding yeast Saccharomyces cerevisiae model organism and this complex consists of five core subunits (Atg1, Atg13, Atg17, Atg29, Atg31). Yet, the orthologous ULK complex from humans has a different subunit composition, and in particular contains a unique component called ATG101 in place of two Atg29 and Atg31. It is unclear how this difference in composition would affect the overall structure and subunit organization as ATG101 shows no sequence nor structural homology to Atg29 and Atg31.

In this publication, we tried to address this fundamental question by characterizing the Atg1 complex from a less widely used model organism fission yeast Schizosaccharomyces pombe which interestingly shows an identical subunit composition to the human ULK complex. Our biochemical data showed that the conserved subunits of the S. pombe Atg1 complex (Atg1, Atg13, Atg17) interact with one another in a similar fashion as their counterparts in the S. cerevisiae Atg1 complex. However, unlike Atg29 and Atg31, S. pombe Atg101 does not bind Atg17 and appears to plays unique functions. Another surprise finding from our study is that S. pombe Atg17 adopts a different overall structure compared to S. cerevisiae Atg17. This finding challenges a previous proposed model in the field by suggesting that the Atg17 family of proteins do not necessary need to adopt an overall “curved” shape to exert its physiological function.

What are the next steps for this research?

A key next step for us would be to determine if our findings in S. pombe would apply to the human ULK complex. We also need to further characterize the mechanism of action of the Atg1/ULK complex and how it regulates the initiation of autophagy.

This research was funded by:

This worked was funded by CIHR.

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