DNA contains the information for making the proteins that our cells need to function normally. This process is known as “gene expression” and our health relies on it being tightly controlled to ensure that the right proteins are made in the right cells, time, and amount.
Gene expression is a two-step process where a transient intermediate called messenger RNA (mRNA) is copied from the DNA and used as a template for making proteins. We aimed at understanding how mRNA fate is controlled. We focus on a class of proteins: “RNA-binding proteins” (RBPs) that can attach to mRNAs, to act as regulators. However, a major gap in our knowledge is how their different functions are controlled such that the correct proteins are synthesised.
We focused on one well-studied multifunctional RBP called poly(A)-binding protein 1 (PABP1), which is a critical regulator of mRNAs. Previous studies established that PABP1 interacts with multiple proteins and that those different partners are involved in PABP1 different functions. However, many partners interact with the same piece of PABP1, making it difficult to understand how it interacts with the correct partner, at the right time. Our previous work had revealed a potential clue as we found that PABP1 is subject to many post-translational modifications (PTMs). Proteins are chains of amino acids (AAs) and PTMs are chemical groups that are added to specific AAs to change their properties. This can for instance block interaction with protein partners. In particular we found that one AA that is key for many partner interactions is subject to more than one type of mutually exclusive PTM. Therefore, we hypothesised that this may provide a “switch” that determines which protein partner interacts with PABP1, hence dictating its function.
Since these types of PTMs have recently been identified in the >1000 human RBPs, our research could provide an important paradigm for how different functions of multifunctional RBPs are co-ordinated to achieve finely tuned gene expression.
Information gained has practical applications. RBPs are important as their dysfunction causes many type of diseases including metabolic, reproductive, neurological and oncogenic disorders. Understanding how they function is a necessary step to understand how they go wrong in disease, and to develop therapeutic compounds.
Knowledge gained can also be used by commercial sectors which rely on biology: Analysis of the EU “bioeconomy” in previous years of has shown it to account for €2.1 trillion annual turnover and 18.3 million jobs.
