**Postdoctoral fellow and graduate student positions available. Please contact Dr. Calvin Yip by e-mail.**
1. Autophagy machinery
How does a cell remove and recycle unwanted materials? Autophagy is an evolutionarily conserved pathway that encapsulates large 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. We study how a specialized group of proteins called Atg proteins mediate the different steps of this important membrane trafficking and degradative pathway using an approach combining biochemistry, structural biology, and cell biology.
Figure 1. Cover art featured in Autophagy highlighting the overall architecture of the yeast core Atg1 complex (Chew et al., 2015).
2. Chromatin modifying complexes
How does a cell establishes and maintains its gene expression pattern and adapts this to different environmental conditions? Eukaryotic genomic DNA exists in a DNA-protein complex known as chromatin. Post translational modifications to the histone proteins that form the nucleosome, the most basic unit of chromatin, is a key mechanism to regulate chromatin structure and gene expression. Using budding yeast as a model, we study how specialized multi-protein chromatin modifying complexes in this organism perform their physiological functions using biochemical and structural biology approaches.
Figure 2. Proposed model of subunit organization of the yeast SAGA histone acetyltransferase complex (Setiaputra et al., JBC 2015)
3. Structural basis of rare diseases
Single particle EM is an advanced molecular imaging technology that allows us to visualize the overall architectures of large proteins and multi-protein assemblies. Recent “revolutionary” advances in this technology have enabled researchers to obtain structural information of biological molecules to near atomic resolution. We are interested in applying this powerful structural approach to analyze dynamic proteins and macromolecular assemblies, particularly those with relevance to rare diseases . This research will be facilitated by the 300kV Titan Krios transmission electron microscope (with Falcon 3 detector) recently acquired by UBC.
Figure 3. Molecular architecture of the Elongator complex obtained by single-particle EM and molecular modeling (Setiaputra et al., EMBO Reports 2017). Mutations to the Elongator complex subunit Elp1 causes the rare disease familial disautonomia.
Setiaputra, D.T., Cheng, D.T., Lu, S., Hansen, J.H., Dalwadi, U., Lam, C.H., To, J.L., Dong, M.Q., Yip, C.K. Molecular architecture of the yeast Elongator complex reveals an unexpected asymmetric subunit arrangment. (2017) EMBO Reports 18: 280-291.
Kim, D., Setiaputra, D., Jung, T., Chung, J., Leitner, A., Yoon, J., Aebersold, R., Hebert, H., Yip, C.K., Song, J.J. Molecular architecture of yeast chromatin assembly factor 1. (2016) Scientific Reports 6: 26702
Chew, L.H., Lu, S., Liu, X., Li, F.K., Yu, A.Y., Klionsky, D.J., Dong, M.Q., Yip, C.K. Molecular interactions of the Saccharomyces cerevisiae Atg1 complex provide insights into assembly and regulator mechanisms. (2015) Autophagy 11: 891-905.
Setiaputra, D., Ross, J.D., Lu, S., Cheng, D.T., Dong, M.Q., Yip, C.K. Conformational flexibility and subunit arrangement of the modular yeast Spt-Ada-Gcn5 acetyltransferase complex. (2015) Journal of Biological Chemistry 290: 10057-10070.
Chew, L.H., Yip, C.K. Structural biology of the macroautophagy machinery. (2014) Frontiers in Biology 9: 18-34.
Chew, L.H., Setiaputra, D., Klionsky, D.J., Yip, C.K. Structural characterization of the Saccharomyces cerevisiae autophagy regulatory complex Atg17-Atg31-Atg29. (2013) Autophagy 9: 1467-1474.
Mao, K., Chew, L.H., Inoue, Y., Cheong, H., Nair, U., Popelka, H., Yip, C.K., Klionsky, D.J. Atg29 phosphorylation regulates coordination of the Atg17-Atg31-Atg29 complex with the Atg11 scaffold during autophagy initiation. (2013) Proceedings of the National Academy of Sciences of the USA 110: E2875-E2884.