Journal Club

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Journal Club: Shark blood compound offers up novel mechanism for stabilizing folded proteins

A compound in the blood of sharks and other marine life has an unusual way of stabilizing proteins. Understanding its mechanism could offer insights into health and disease. Image: Shutterstock/wildestanimal

A compound in the blood of sharks and other marine life has an unusual means of stabilizing proteins. Understanding its mechanism could offer insights into health and disease.
Image: Shutterstock/wildestanimal

Sharks and other sea life often maintain high levels of trimethylamine N-oxide (TMAO) in their blood, a compound vital to their surviving in the saline environment. TMAO helps maintain an osmotic balance between body tissues and sea water to prevent dehydration. It also counteracts the protein-denaturing effects of sea water and of the blood’s other osmoregulating compounds.

In a recent study in PNAS, researchers from The Pennsylvania State University reveal a partial explanation for how TMAO does its job. Using computer models that simulate molecular interactions, and working with an artificial protein called elastin-like polypeptide (ELP), the researchers demonstrate that TMAO operates in a completely different manner than other protein-stabilizing molecules, called osmolytes. “TMAO is in everything from shark’s blood to the human liver,” says Penn State biointerfaces researcher Paul Cremer, a study co-author. “So if we can understand its mechanism, perhaps we can shed light on its behavior in health and disease.”

The researchers compared the behavior of TMAO with that of two other osmolytes when each was exposed to an air-water interface – used as a surrogate for notoriously difficult to observe hydrophobic protein-water interfaces. They observed that whereas the osmolytes betaine and glycine increased the surface tension between air and water, TMAO decreased it, suggesting that TMAO employs a distinct protein-stabilizing mechanism.

Computer simulations of TMAO’s interactions with ELP provided further evidence of a distinct TMAO mechanism. The simulations, which use known properties of particles in motion to predict how molecules will behave when they interact, determined that the osmolyte may accumulate at the surface of ELP. That’s in stark contrast to betaine and glycine, which typically flee the surface of proteins. “Normally you’d think that things that run to the surface of a protein would denature it, but that’s not the case with TMAO,” says Penn State chemist William Noid, one of the study’s co-authors.

But there’s another twist to this unfolding story. “The most interesting part of the story is another type of mechanism that [the authors] refute,” says Nico van der Vegt, professor of chemistry at the Technical University of Darmstadt, Germany, who was not involved in the study. Using infrared spectroscopy, the authors showed that TMAO does not, as many had thought, stabilize proteins indirectly by altering the strength of hydrogen bonds between surrounding water molecules. Instead, TMAO binds directly, and very tightly, to water molecules, thereby influencing water’s interactions with the protein.

Because many of the study’s results are based on simulations, it’s still not entirely clear how TMAO binds to proteins and surrounding water molecules to maintain proteins in a folded state—nor is it clear why this molecule appears to be unique among osmolytes. Further research using more realistic protein models is needed. But for now, the researchers propose a hypothesis: TMAO may act as a surfactant, reducing the surface tension of water so that proteins may remain folded.

“I think the paper brings a nice suggestion for the protein stabilizing mechanism of TMAO,” says Pavel Jungwirth, research group head at the Academy of Sciences of the Czech Republic, who was not involved in the work. “But, as also stated directly in the paper, lacks the ultimate proof. So clearly more work is needed to sort it out.”

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