Researchers discover the largest protein ever found in biology

At UC San Diego's Scripps Institution of Oceanography, scientists have made a groundbreaking discovery while investigating how marine algae produce their complex toxins. The research has led to the identification of the largest protein ever found in biology. This discovery not only uncovers the biological mechanisms that algae have evolved to create these toxins but also reveals new strategies for assembling chemicals, potentially unlocking advancements in medicine and materials science.

In their quest to understand how a type of algae, Prymnesium parvum, produces its toxin—a substance known for causing massive fish kills—researchers stumbled upon a colossal protein they’ve named PKZILLA-1. This protein is not just large; it is a record-breaker. At 25% larger than titin, the previous record-holding protein found in human muscles, PKZILLA-1 is indeed a behemoth. Bradley Moore, a marine chemist at Scripps Oceanography and the Skaggs School of Pharmacy and Pharmaceutical Sciences, describes it as “the Mount Everest of proteins,” emphasizing that this discovery broadens our understanding of biological capabilities.

The study, published in Science and funded by the National Institutes of Health and the National Science Foundation, highlights that PKZILLA-1, along with another sizeable protein PKZILLA-2, is crucial for the production of prymnesin—the complex molecule responsible for the algae’s toxic effects. The research didn’t just stop at identifying these massive proteins; it also uncovered unusually large genes within Prymnesium parvum that serve as blueprints for these proteins.

These findings could significantly enhance monitoring efforts for harmful algal blooms. By focusing on detecting the genes responsible for toxin production rather than the toxins themselves, you could potentially identify blooms before they become problematic. As Timothy Fallon, a postdoctoral researcher at Scripps and co-first author of the study, points out, "Monitoring for the genes instead of the toxin could allow us to catch blooms before they start instead of only being able to identify them once the toxins are circulating."

The discovery of PKZILLA-1 and PKZILLA-2 has also provided insights into the algae’s complex cellular machinery for toxin production. Understanding how these intricate toxins are assembled could be instrumental for scientists looking to synthesize new compounds for medical or industrial use. Moore elaborates on this potential, stating, “Understanding how nature has evolved its chemical wizardry gives us as scientific practitioners the ability to apply those insights to creating useful products, whether it’s a new anti-cancer drug or a new fabric.”

Prymnesium parvum, often referred to as golden algae, is a single-celled organism that thrives in both freshwater and saltwater environments worldwide. When these algae bloom, they can lead to devastating fish die-offs due to the prymnesin toxin, which severely damages the gills of fish and other aquatic life. In 2022, for instance, a golden algae bloom led to the death of 500-1,000 tons of fish in the Oder River between Poland and Germany, showcasing the destructive potential of these microorganisms. This toxin belongs to a group known as polyketide polyethers, which includes other notable toxins like brevetoxin B, a red tide toxin in Florida, and ciguatoxin, which affects reef fish in the South Pacific and Caribbean.

Despite being one of the largest and most complex chemicals in biology, researchers have long struggled to understand how microorganisms like Prymnesium parvum produce such intricate molecules. Starting in 2019, Moore, Fallon, and Vikram Shende, another postdoctoral researcher at Scripps and co-first author of the paper, set out to decode the biochemical and genetic processes behind the production of prymnesin.

The team began by sequencing the golden algae’s genome to identify the genes involved in prymnesin production. Traditional genome searching methods didn’t yield results, leading the team to adopt alternative techniques better suited for finding extremely long genes. Their persistence paid off. “We were able to locate the genes, and it turned out that to make giant toxic molecules, this alga uses giant genes,” explains Shende.

With the PKZILLA-1 and PKZILLA-2 genes identified, the researchers then needed to determine what these genes produce. Fallon describes how the team translated the genes' coding sequences, similar to reading sheet music, into a sequence of amino acids that formed the protein.

Upon completing the assembly of the PKZILLA proteins, the researchers were astonished by their size. PKZILLA-1, in particular, broke the record with a mass of 4.7 megadaltons, while PKZILLA-2 wasn’t far behind at 3.2 megadaltons. For context, titin, the previous record-holder, can reach up to 3.7 megadaltons, which is about 90 times larger than a typical protein.

Further tests confirmed that golden algae indeed produce these giant proteins in nature, prompting the team to investigate whether these proteins are involved in toxin production. As enzymes, the PKZILLA proteins initiate chemical reactions, and the researchers meticulously mapped out the 239 chemical reactions involved in producing prymnesin. The outcome matched the structure of prymnesin perfectly, confirming their role in toxin production.

This discovery has opened the door to understanding previously unknown chemical assembly strategies in nature, as Moore suggests. The knowledge gained could lead to new chemical possibilities in laboratories, potentially contributing to the development of future medicines and materials.

Finding the genes responsible for prymnesin production also holds promise for improving monitoring techniques for golden algae blooms. Similar to PCR tests used during the COVID-19 pandemic, environmental tests could be developed to detect the PKZILLA genes, offering a cost-effective way to monitor and study the conditions that lead to these harmful blooms.

Fallon notes that the PKZILLA genes are the first ever to be causally linked to the production of any marine toxin in the polyether group, a significant milestone in marine biology. The team now aims to apply the same screening techniques to other species that produce polyether toxins. If successful, they could unlock similar genetic monitoring possibilities for a range of harmful algal blooms with substantial global impacts, such as those caused by ciguatoxin, which may affect up to 500,000 people annually.

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