New insights into the capacity of mirror image proteins to interact
At least 1 % of adults over the age of 60 will be diagnosed with Parkinson’s disease, a neurological disorder that impacts one’s ability to move. While what causes Parkinson’s remains unknown, scientists do have some clues to work with. “A hallmark of the disease is the formation of aggregates of the protein alpha-synuclein in inclusion bodies known as Lewy bodies,” says Birthe Brandt Kragelund, a professor of Biomolecular Sciences at the University of Copenhagen. With the support of the EU-funded SYN-CHARGE project, Kragelund, together with researcher Estella Newcombe, originally set out to determine whether the proteins involved in Parkinson’s disease pathology could undergo a highly charged, disordered interaction with part of a calcium pump, thus causing its activation.
Challenging what we know about protein interactions
But sometimes research decides to take you in a different direction. So, when Kragelund and Newcombe discovered that their original plan was a dead end, they changed course. “While still interesting, the original focus wasn’t going to lead us much further, so we made changes,” explains Newcombe. Instead of looking at a specific interaction, the project, which received support from the Marie Skłodowska-Curie Actions programme, pivoted to studying this type of interaction within the context of different protein systems. “We ended up testing whether disordered proteins could interact with their mirror image enantiomers,” adds Kragelund. Perhaps this pivot was a blessing in disguise, as it turned out that the new line of research led to a breakthrough finding – one that challenges what we know and assume about protein interactions. According to Newcombe, it wasn’t that surprising that structured proteins could not interact with the mirror image of their binding partner, as this alters how the proteins fit together. “However, when it comes to disordered proteins, they can interact as though nothing is different,” she says. “What makes this finding interesting is that it contradicts preconceived notions about mirror image proteins’ capacity to interact.”
Opening the door to developing new drugs and therapies
Finding that mirror image enantiomers can interact when the protein binding partners are disordered opens the door to using enantiomers to target disordered proteins in disease. “Peptide-based therapies are increasingly being studied, and our work positions D-peptides as an interesting option as they are not readily degraded by the proteolytic activity of biological systems,” notes Newcombe. “By showing that L- and D-proteins can interact in certain conditions, we have pushed the boundaries of what we know about protein biochemistry,” adds Kragelund. The project published a paper covering some of its results, while Newcombe discussed the topic on a podcast about neurodegenerative disease proteins. Both Kragelund and Newcombe plan to continue their work in the field, with Newcombe recently taking a job at a pharmaceutical company and Kragelund continuing her efforts in the lab.
Keywords
SYN-CHARGE, mirror image proteins, Parkinson’s disease, protein, disordered proteins, protein interactions