Nearly a third of all human proteins must fold correctly inside a cellular compartment called the endoplasmic reticulum (ER) before they can function. When this folding process fails, it contributes to several chronic diseases. Yet scientists still do not understand the basic molecular steps that control it. This project tackles five unanswered questions about how proteins fold in the ER. The key players are members of the protein disulfide isomerase family, which help form disulfide bonds—chemical links that stabilise protein shape. Researchers also want to know how the ER maintains its unique chemical environment, what other chemical modifications happen to protein thiol groups, where those modifying chemicals come from, and which enzymes reverse the modifications. This is fundamental science. It will not produce a drug or a diagnostic test in the near term. But without knowing how the protein folding machinery works at the molecular level, researchers cannot rationally design treatments for diseases where folding goes wrong—such as cystic fibrosis, certain neurodegenerative disorders, and some forms of diabetes. Past work on similar fundamental questions about protein folding has already led to unexpected insights into how cells manage stress and quality control, laying groundwork for future therapeutic strategies.
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How are protein thiol groups modified in the endoplasmic reticulum during protein folding and cell stress? The folding and assembly of proteins within the endoplasmic reticulum (ER) is an essential process for normal healthy tissues. Breakdown in this process leads to several chronic diseases so it is critical that we have a better understanding of the molecular details of how cells fold proteins that enter the secretory pathway. Nearly a third of all proteins coded for by the human genome enter the secretory pathway and undergo disulfide formation during their folding. We know that members of the protein disulfide isomerase family catalyse disulfide formation but we know little about the function of each of the family members or how the unique redox environment of the ER is maintained. In addition, a variety of modifications to thiol groups can regulate protein function yet we know very little about the targets of these modifications in the ER or their consequence on protein fu nction. This proposal aims to dissect the molecular mechanisms involved in this process by investigating key questions concerning disulfide formation and thiol modification that remain unanswered. Specifically these include: How are the redox conditions in the endoplasmic reticulum balanced to allow correct folding and assembly of proteins entering the secretory pathway? What is the specific role of protein disulfide isomerase family members during protein folding and degradation? What are the targets for reversible thiol modification in the ER? What are the sources and levels of thiol-modifying chemicals? Which enzymes catalyse the reversal of thiol modification? The results from this work will impact on our understanding of how the cellular protein folding machinery functions and will clarify the role of thiol modification of proteins within the ER.
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