Protein transport and quality control in the secretory pathway View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2015-

FUNDING AMOUNT

3778065.0 GBP

ABSTRACT

The cells that make up our bodies are powered by protein machines. Like many machines, proteins form complex structures that have the potential to mis-assemble. When faulty structures are formed, they can have detrimental effects and lead to various diseases like cystic fibrosis and neurodegenerative conditions. We study how cells operate a “quality control” system that surveys proteins to ensure that only properly assembled structures are deployed. An additional aspect of our research is in understanding how the specific location of these protein machines is governed so that the right protein gets to the right place at the right time. Our studies use the baker’s yeast, Saccharomyces cerevisiae, as a model system, which allows us to use a combination of genetics and biochemistry to understand the molecular details of cellular protein quality control. Technical Summary A key component of cellular physiology is the accurate deployment of every gene product to the correct cellular compartment. Fully one third of the proteins encoded in eukaryotic genomes navigate the secretory pathway, entering this system via the endoplasmic reticulum (ER). Research in the Miller lab is broadly aimed at understanding basic mechanisms of secretory protein biogenesis, focusing on aspects of protein quality control within the ER. We use the budding yeast, Saccharomyces cerevisiae, as a model system, which affords facile biochemical, genetic, genomic and proteomic tools that can be brought to bear on this fundamental biological problem. By using such a tractable model system, we can rapidly discover new pathways and dissect mechanisms that may be directly relevant to a number of human diseases, most notably cystic fibrosis and similar diseases of protein misfolding. The molecular basis for vesicle formation from the ER is relatively well understood and relies on cytoplasmic coat proteins known as the COPII coat. Yet, despite a relatively deep understanding of the mechanisms that drive COPII vesicle formation and cargo capture, we know very little about how this process is regulated to prevent improper traffic of misfolded proteins. We study this problem from two angles: a “cargo-centric” approach examining the folding and trafficking of an individual protein, and a systems-level approach to characterize quality control more broadly. We use high throughput yeast genetics to identify new components that act in various aspects of protein quality control, and biochemical approaches to dissect mechanism. One long-term goal is to understand how vesicle abundance and architecture can adapt to changing physiological needs with respect to cargo load. More... »

URL

https://gtr.ukri.org/project/74F33EC5-3F23-4C9F-99C7-4513CEFB6867

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