Grant: Operating Grant

The outer cell membrane holds cells together and creates a barrier to the outside world. The membranes inside cells enclose chemical reactions that would harm the cells. However, cells must be able to move things across these membranes and therefore complex machinery exists that inserts proteins into membranes so cells can pass signals, small molecules and other proteins across the membranes. For many proteins, we now have a good understanding of the machinery that inserts them into membranes. However, there is a class of proteins, called tail-anchor proteins, about which we know very little. We and others have found that tail-anchor proteins are involved in a wide variety of crucial cellular processes. They have also been linked to a number of diseases states including diabetes, myotonic dystrophy, (ALS) Lou Gehrig's disease and, most relevant to this proposal, are cancer and auto-immune diseases. To better understand these proteins, we have used bioinformatics, biochemical and cell biology approaches to identify all of the tail-anchor proteins in humans and plants. We propose to continue this work to refine our identification and assign these proteins to specific sub-classes to help understand how these proteins function. We propose testing many different variations of the sequence within tail-anchor proteins that targets them to membranes to derive a signature sequence that specifies transport to the correct membrane. We propose extending the image-based genetic screening approach we have used to study membrane assembly to identify the machinery that inserts tail-anchor proteins in membranes. Finally, we propose to study in detail the role of the tail-anchor sequence for a class of proteins involved in cancer and auto-immune diseases.