A groundbreaking international study led by the Earth-Life Science Institute (ELSI) at Tokyo Institute of Science, in collaboration with the Hebrew University of Jerusalem and the Weizmann Institute of Science, has revealed that an ancient protein motif can bind both natural and mirror-image nucleic acids. This “ambidextrous” property, never observed in nucleic acid-binding proteins, offers fresh perspectives on the origins and evolution of life on Earth.
What is Molecular Handedness (Chirality)?
Molecules, like human hands, exist in “right-handed” and “left-handed” forms-mirror images known as chiral forms. Life on Earth strongly favours specific handedness: proteins are made from left-handed amino acids, and nucleic acids (DNA and RNA) from right-handed sugars. This preference, called homochirality, is fundamental to biology. Typically, reversing a molecule’s handedness renders it non-functional in living systems, leading scientists to believe that mirror-image proteins cannot perform normal biological roles.
Key Discovery: The Helix-Hairpin-Helix (HhH) Motif’s Functional Ambidexterity
The research team, including Prof. Liam M. Longo and Tatsuya Corlett (ELSI), Prof. Norman Metanis and Dr Orit Weil-Ktorza (Hebrew University), and Prof. Yaakov Levy and colleagues (Weizmann Institute), challenged this assumption. Their study, published in Angewandte Chemie, focused on the helix-hairpin-helix (HhH) motif-a primordial and widely conserved protein structure known for binding DNA and RNA.
Remarkably, the team found that a chemically synthesised mirror-image version of the HhH motif also binds nucleic acids. This “functional ambidexterity” is akin to a glove fitting both hands, and is the first such finding for a nucleic acid-binding protein.
Experimental Findings
Despite double-stranded DNA’s right-handed structure, the mirror-image HhH motif was able to bind effectively. Laboratory tests confirmed this binding, and further analysis showed that both natural and mirror-image proteins used similar regions for nucleic acid interaction. Molecular simulations revealed that, although binding modes differed, the underlying mechanisms were linked at the molecular level.
Evolutionary Implications
This discovery raises important questions: Why did this protein motif evolve to be ambidextrous? One possibility is that it needed to bind various DNA structures or move along DNA molecules. More intriguingly, it could suggest that early evolutionary pressures once favoured such ambidexterity, perhaps even hinting at ancient mirror-image life forms. While these ideas remain speculative, the study opens new avenues for exploring protein evolution and the origins of life.
Conclusion
This study marks the first demonstration of an “ambidextrous” protein binding both natural and mirror-image nucleic acids, challenging long-held assumptions about protein function and molecular evolution. The findings deepen our understanding of protein evolution, molecular chirality, and the fundamental chemistry of life.
Image title: The (HhH)2-Fold is Functionally Ambidextrous
Credit: Liam M. Longo License: CC BY-NC-ND