Researchers found a rare example of an ancient protein that can still function in a molecular mirror world – offering new clues about the evolutionary history of proteins that bind to nucleic acids. But many mysteries remain. An international team of scientists has shown that a simple, ancient protein, used by all life to latch onto DNA and RNA, still works even when its molecular “handedness” is flipped. This surprising discovery marks the first documented example of nucleic acid-binding proteins that can operate in a mirror world, offering fresh insights into the evolution of nucleic acid binding and the history of Earth-like molecular handedness.
A new study led by researchers from the Earth-Life Science Institute (ELSI) at the Institute of Science Tokyo, in collaboration with the Hebrew University of Jerusalem and the Weizmann Institute of Science, found that an ancient protein motif that binds to nucleic acids is functionally “ambidextrous.” This means that the motif can interact with both natural and mirror-image nucleic acids, an occurrence that has never before been reported for nucleic acid binding. The study provides a unique snapshot of protein evolution and raises intriguing questions about the origins and history of life on Earth.
Like the human hand, many molecules exist in “right-handed” and “left-handed” forms that are mirror images of each other. Life on Earth has a strong preference for molecular handedness: proteins are made up of left-handed amino acids, while nucleic acids are made up of right-handed sugars. This phenomenon, called homochirality, is a fundamental feature of biology as we know it. With few exceptions, flipping the handedness of a complex molecule causes it to fall out of step with Earth life and to stop functioning. It is kind of like Alice stepping through the looking glass into a world quite unlike her own. This fact has led to a long-standing view that mirror-image proteins cannot perform their normal biological function.
New research led by Prof. Liam M. Longo, Specially Appointed Associate Professor and Master’s student Tatsuya Corlett at ELSI, in collaboration with Prof. Norman Metanis and Dr. Orit Weil-Ktorza at the Hebrew University of Jerusalem and Prof. Yaakov (Koby) Levy, PhD. Student Segev Naveh-Tassa, Dr. Yael Fridmann-Sirkis, Dr. Dragana Despotović, and Dr. Kesava Phaneendra Cherukuri at the Weizmann Institute of Science, has challenged this assumption. In the study, published in the journal Angewandte Chemie, the researchers reported that a primordial and widely conserved protein structure called the helix-hairpin-helix (HhH) motif is capable of functioning in both left- and right-handed forms. In its natural state, the HhH motif binds to DNA and RNA. Surprisingly, the researchers found that a chemically synthesized mirror image of the motif is also functional—a phenomenon the authors refer to as functional ambidexterity. In simple terms, the HhH motif is like a glove that fits snuggly on both hands. No such nucleic-acid binding protein has been reported before.
Double stranded DNA has a right-handed twist, so the reasonable expectation was that a mirror-image protein would be unable to bind. “I was looking at the motif – just playing around on the computer – and I suddenly thought: This motif can bind mirror-DNA!” said Longo. “It was a crazy idea,” said Metanis, a peptide chemist, ‘but the more we looked at the structure, the more we thought that maybe we were on to something.” To investigate whether the mirrored HhH motif-containing proteins bind to double stranded DNA, they synthesized the mirror-image protein and measured its binding in the lab. Sure enough, binding was detected.
But was binding of the mirror-image protein similar to the natural protein? To test this, the researchers analyzed the kinetics of un-binding, as well as the effect of several mutations. And both approaches suggested surprising similarities. Encouraged by these results, Longo reached out to Levy, a computational chemist who could use molecular simulations to paint a detailed molecular picture of the binding process. What the researchers found surprised them: Although there were differences in how the natural and mirror-image proteins bound to DNA, similar regions of the protein were responsible for binding in each case. In other words, these two binding modes were linked to each other at the molecular level.
This study is an exciting first example of ambidextrous proteins binding to nucleic acids, and raises more questions than it answers. What forces caused this protein to be ambidextrous in the first place? “We still don’t know,” says Metanis. “Perhaps it reflects the need for this domain to bind multiple types of DNA structures, or to slide along the DNA molecule.” Or, perhaps it is pointing to an even greater evolutionary mystery: “The most intriguing explanation is that functional ambidexterity was once under selective pressure, perhaps due to ancient mirror-image life!” said Longo with a smile. But the authors caution that we are still a long ways away from being able to draw such provocative conclusions. For now, the hunt for other ambidextrous proteins begins!
Image:
Title: The (HhH)2-Fold is Functionally Ambidextrous
Caption: A simplified (HhH)2-Fold protein binding to natural and mirror-image dsDNA. The binding surface between the two binding modes is partially overlapping
Credit: Liam M. Longo License: CC BY-NC-ND
The research paper titled “Functional Ambidexterity of an Ancient Nucleic Acid-Binding Domain” is now available in Angewandte Chemie and can be accessed at https://doi.org/10.1002/anie.202505188
Researchers:
Orit Weil-Ktorza1, Segev Naveh-Tassa2, Yael Fridmann-Sirkis3, Dragana Despotović4,5, Kesava Phaneendra Cherukuri4, Tatsuya Corlett6, Yaakov Levy2, Norman Metanis1, Liam M. Longo6,7
Institutions
1. Institute of Chemistry, The Center for Nanoscience and Nanotechnology, Casali Center of Applied Chemistry, The Hebrew University of Jerusalem
2. Department of Chemical and Structural Biology, Weizmann Institute of Science
3. Department of Life Sciences Core Facilities, Weizmann Institute of Science
4. Department of Biomolecular Sciences, Weizmann Institute of Science
5. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade
6. Earth-Life Science Institute, Institute of Science Tokyo, Japan
7. Department Blue Marble Space Institute of Science, Seattle, Washington
Earth-Life Science Institute (ELSI) is one of Japan’s ambitious World Premiere International research centers, whose aim is to achieve progress in broadly inter-disciplinary scientific areas by inspiring the world’s greatest minds to come to Japan and collaborate on the most challenging scientific problems. ELSI’s primary aim is to address the origin and co-evolution of the Earth and life.
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”
World Premier International Research Center Initiative (WPI) was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).
For a century, the Hebrew University of Jerusalem has been a beacon for visionary minds who challenge norms and shape the future. Founded by luminaries like Albert Einstein, who entrusted his intellectual legacy to the university, it is dedicated to advancing knowledge, fostering leadership, and promoting diversity. Home to over 23,000 students from 90 countries, the Hebrew University drives much of Israel’s civilian scientific research, with over 11,000 patents and groundbreaking contributions recognized by nine Nobel Prizes, two Turing Awards, and a Fields Medal. Ranked 81st globally by the Shanghai Ranking (2024), it celebrates a century of excellence in research, education, and innovation. To learn more about the university’s academic programs, research, and achievements, visit the official website at http://new.huji.ac.il/en.
The Weizmann Institute of Science is one of the world’s leading multidisciplinary basic research institutions in the natural and exact sciences. It is located in Rehovot, Israel, just south of Tel Aviv. It was initially established as the Daniel Sieff Institute in 1934, by Israel and Rebecca Sieff of London in memory of their son Daniel. In 1949, it was renamed for Dr. Chaim Weizmann, the first President of the State of Israel and Founder of the Institute https://www.weizmann.ac.il