Estudio de proteínas antiguas aclara el misterio de la hemoglobina única de los cocodrilos

Crocodile With Impala

Cocodrilo Con Impala

Un cocodrilo del Nilo se traga un impala, su recompensa por acechar bajo la superficie del agua. Al resucitar la hemoglobina de los antiguos ancestros de los cocodrilos, un equipo dirigido por Husker ha ayudado a explicar por qué otros vertebrados no lograron desarrollar las adaptaciones que permiten a los cocodrilos pasar horas sin aire. Crédito: Prensa celular / Biología actual / Shutterstock / Scott Schrage, Universidad de Nebraska–Lincoln

Los experimentos con proteínas antiguas revelan que las mutaciones son más numerosas y matizadas de lo que se creía.

Puede avanzar a más de 50 millas por hora, saltando más de 30 pies en un solo salto. Pero ese atletismo de la medalla de platino se queda en el camino en la orilla de un río subsahariano, la fuente de vida o muerte para el impala asustadizo que se calma para tomar una copa a 100 grados de temperatura.

Durante la última hora, un cocodrilo del Nilo ha estado al acecho en silencio en el río fangoso. Cuando el depredador ápice ataca, sus poderosas mandíbulas se sujetan a los cuartos traseros de un impala desprevenido con una fuerza de 5000 libras. El arma real, sin embargo, es el agua misma, ya que el cocodrilo arrastra a su presa a la parte más profunda para ahogarla.

El éxito de la emboscada del cocodrilo radica en los tanques de buceo nanoscópicos (hemoglobinas) que recorren su torrente sanguíneo, descargando oxígeno de los pulmones a los tejidos a un ritmo lento pero constante que le permite pasar horas sin aire. La hipereficiencia de esa hemoglobina especializada ha llevado a algunos biólogos a preguntarse por qué, de todos los

Los vertebrados son animales que tienen columna vertebral e incluyen mamíferos, aves, reptiles, anfibios y peces. Tienen un sistema nervioso más avanzado que los invertebrados, lo que les permite un mayor control sobre sus movimientos y comportamientos, y son capaces de moverse y soportar su peso corporal utilizando su columna vertebral. Los vertebrados se encuentran en muchos hábitats y juegan un papel importante en el ecosistema como depredadores, presas y carroñeros.

» datos-gt-translate-atributos=»[{» attribute=»»>vertebrates in all the world, crocodilians were the lone group to hit on such an optimal solution to making the most of a breath.

By statistically reconstructing and experimentally resurrecting the hemoglobin of an archosaur, the 240-million-year-old ancestor of all crocodilians and birds, the University of Nebraska–Lincoln’s Jay Storz and colleagues have gleaned new insights into that why. Rather than requiring just a few key mutations, as earlier research suggested, the unique properties of crocodilian hemoglobin stemmed from 21 interconnected mutations that litter the intricate component of red blood cells.

That complexity, and the multiple knock-on effects that any one mutation can induce in hemoglobin, may have forged an evolutionary path so labyrinthine that nature failed to retrace it even over tens of millions of years, the researchers said.

“If it was such an easy trick — if it was that easy to do, just making a few changes — everyone would be doing it,” said Storz, a senior author of the study and Willa Cather Professor of biological sciences at Nebraska.

All hemoglobin binds with oxygen in the lungs before swimming through the bloodstream and eventually releasing that oxygen to the tissues that depend on it. In most vertebrates, hemoglobin’s affinity for capturing and holding oxygen is dictated largely by molecules known as organic phosphates, which, by attaching themselves to the hemoglobin, can coax it into releasing its precious cargo.

But in crocodilians — crocodiles, alligators, and their kin — the role of organic phosphates was supplanted by a molecule, bicarbonate, that is produced from the breakdown of carbon dioxide. Because hardworking tissues produce lots of carbon dioxide, they also indirectly generate lots of bicarbonate, which in turn encourages hemoglobin to dispense its oxygen to the tissues most in need of it.

“It’s a super-efficient system that provides a kind of slow-release mechanism that allows crocodilians to efficiently exploit their onboard oxygen stores,” Storz said. “It’s part of the reason they’re able to stay underwater for so long.”

As postdoctoral researchers in Storz’s lab, Chandrasekhar Natarajan, Tony Signore, and Naim Bautista had already helped decipher the workings of the crocodilian hemoglobin. Alongside colleagues from Denmark, Canada, the United States, and Japan, Storz’s team decided to embark on a multidisciplinary study of how the oxygen-ferrying marvel came to be.

Prior efforts to understand its evolution involved incorporating known mutations into human hemoglobin and looking for any functional changes, which were usually scant. Recent findings from his own lab had convinced Storz that the approach was flawed. There were plenty of differences, after all, between human hemoglobin and that of the ancient reptilian creatures from which modern-day crocodilians evolved.

“What’s important is to understand the effects of mutations on the genetic background in which they actually evolved, which means making vertical comparisons between ancestral and descendant proteins, rather than horizontal comparisons between proteins of contemporary

Comparing the hemoglobin blueprints of the archosaur and crocodilian ancestors also helped identify changes in

Storz said the findings speak to the fact that a combination of mutations might yield functional changes that transcend the sum of their individual effects. A mutation that produces no functional effect on its own might, in any number of ways, open a path to other mutations with clear, direct consequences. In the same vein, he said, those later mutations might influence little without the proper stage-setting predecessors already in place. And all of those factors can be supercharged or waylaid by the environment in which they unfold.

“When you have these complex interactions, it suggests that certain evolutionary solutions are only accessible from certain ancestral starting points,” Storz said. “With the ancestral archosaur hemoglobin, you have a genetic background that makes it possible to evolve the unique properties that we see in hemoglobins of modern-day crocodilians. By contrast, with the ancestor of mammals as a starting point, it may be that there’s some way that you could evolve the same property, but it would have to be through a completely different molecular mechanism, because you’re working within a completely different structural context.”

For better or worse, Storz said, the study also helps explain the difficulty of engineering a human hemoglobin that can mimic and approach the performance of the crocodilian.

“We can’t just say, ‘OK, it’s mainly due to these five mutations. If we take human hemoglobin and just introduce those mutations, voilà, we’ll have one with those same exact properties, and we’ll be able to stay underwater for two hours, too,’” Storz said. “It turns out that’s not the case.

“There are lots of can’t-get-there-from-here problems in the tree of life.”

Reference: “Evolution and molecular basis of a novel allosteric property of crocodilian hemoglobin” by Chandrasekhar Natarajan, Anthony V. Signore, Naim M. Bautista, Federico G. Hoffmann, Jeremy R.H. Tame, Angela Fago and Jay F. Storz, 21 December 2022, Current Biology.
DOI: 10.1016/j.cub.2022.11.049

The study was funded by the National Science Foundation and the National Institutes of Health.

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