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Cell Biology

The deconstruction of Proteins

Compartments that deconstruct proteins identified in the cell nucleus

Microgram/Robert HookeFirst image: cork cells viewed by Hooke and published in 1664 in the book “Micrographia”Microgram/Robert Hooke

During the four years he worked at Harvard University’s Medical School in Boston, United States, and, later on, when he was a professor at the Medical School of the University of São Paulo (USP) in the city of Ribeirão Preto, Marcelo Damário Gomes conducted research showing that the cell nucleus – and not only the cytoplasm that involves the nucleus – houses compartments that destroy unsuccessful proteins or proteins that have already played out their role, before leading the organism into chaos. Thanks to this type of research work, Gomes has a personal story combining the exploration of scientific and existential arenas – sometimes tiny and sometimes broad – allowing him to contribute to the refining of the image of the cell nucleus and to the dream of a manned trip to Mars.

The effort of this and of other research groups has undone the well-known image of the nucleus as the exclusive territory of chromosomes, the long chains of structures and DNA; the sequencing of the genes regulates the production of proteins that form organisms. This comprises the nucleolus, which produces one of the RNA molecules, which in turn produces proteins. The nucleus contains at least ten other compartments – or organelles. Gomes discovered one of them, named fand. Presented in February in Molecular Biology of the Cell, the fand, curiously enough, is limited to itself, and has no outer membrane such as the one separating the nucleus from the cytoplasm. The fands contain proteins called ubiquitins which, together with other proteins, eliminate the proteins that have become useless for the body. Gomes compares this to “a dismantling line” and explores the path opened up three centuries ago by British naturalist, astronomer, and architect Robert Hooke, the first person to study a cell under a rudimentary microscope.

“Nothing is static in the nucleus,” he states. Proteins that come and go all the time control the splitting of the chromosomes, the quality and the recombination of genes and the formation of other cells – in short, the continuity or the end of living things. Six years ago, a team from Lisbon University identified the first of these nucleus compartments, containing proteins that eliminate other proteins; this compartment, referred to as a clastosome, contains specific proteins. Until that time, similar substructures had been found only in the cytoplasm, which involves the nucleus and the other cell compartments.

Under the guidance, recommendations and suggestions of Alfred Lewis Goldberg, an American biochemist who twenty years ago discovered one of the essential selective destruction mechanisms of proteins, the joint effort of Gomes and two other physicians – the United States’ Stewart Harris Lecker and Great Britain’s Thomas Jagoe – spread to other fields of research. Concurrently with a group from a pharmaceutical company that had achieved the same results independently, they identified the atrogin enzyme, which links the ubiquitins to proteins in the muscle, leading to the loss of muscle mass, a common occurrence in some types of cancer, kidney diseases, diabetes and even when an arm or a leg remain in a cast for weeks. In 2001, when this study was published in a scientific journal, Goldberg and his team had already been granted an award by Nasa, the U.S. space agency, for having shown the origin of a problem whose solution could facilitate the desired manned trips to Mars; trips which take one year to get to their destination and one year to come back. “Because of the absence of gravity in outer space,” says Gomes, “an astronaut loses 5% of muscle mass a week.”

Studies on these protein degradation mechanisms have intensified especially after 2004, when two Israeli scientists and one U.S. scientist shared the Nobel Prize for chemistry for their work on proving the role of ubiquitin in the selective elimination of plant and animal proteins. Referred to as proteosome, this cleaning mechanism only goes into action when it identifies proteins that carry at least four strands of ubiquitins. The ubiquitins, so called because they are ubiquitous, act like labels, labeling what must die (an animation of this mechanism, called Kiss of Death, is found here). Gomes had already left Harvard when he heard that Goldberg, one of his favored candidates for the Nobel Prize for having helped identify ubiquitin, was not among the nominees.

Ubiquitin and genes
Formed in the cytoplasm, ubiquitins spread themselves and circulate constantly through all the cells with a nucleus, such as the majority of the cells that make up the human body, with the exception of red blood cells. Some ubiquitins that go through the membrane of the nucleus turn into key characters for the cleaning of the organism, when they form the fand. “The proteosome only recognizes the proteins that have a chain of at least four ubiquitins,” says Gomes. But the ubiquitins are not only the executioners that take the condemned by their hands and lead them to their deaths in a kind of shredder. According to Gomes, proteins called suicidal transcriptions, which regulate gene activity, only function after they get the ubiquitins. “This is a way to ensure that the transcription factors will have a short life and will be destroyed after playing their role only once,” he says. “Everything is highly regulated inside the cell.”

The interaction between ubiquitin and proteosome, the set of proteins that cleanses the body of useless elements, explains to some extent the development of illnesses due to an accumulation of malformed proteins. This is the case, Gomes points out, of Huntington’s Chorea, which worsens as the residues that the proteosome is unable to recognize or eliminate accumulate. In an article published in February of this year in Cellular & Molecular Biology Letters, Halina Ostrowska, a biologist from Poland’s University of Bialystok, shows how this mechanism – because it is linked to the degradation of the majority of the intracellular proteins, including those that control the multiplication and the death of cells – is also a valuable target for new anti-cancer and anti-inflammatory drugs. This seems like a real possibility: in less than 10 years, the work of Goldberg and other pioneers in this field led to the development of Bortezomib, a compound approved in 2005 for the treatment of multiple myelomas.

Gomes’s personal history is similar to that of the target of his studies. Encouraged by his father, who descended from one of the first Spanish and Portuguese families who chased away the “Coroados” [a native tribe], axed the forests and started planting coffee in the northeast of the State of São Paulo, Gomes left his native city of Penapolis when he graduated from high school. Penapolis is celebrating its hundredth anniversary this year. He then studied in the city of Londrina, state of Paraná, and after that moved to São Paulo. But he did not settle down. The atavistic impulse of the Iberian explorers led him to the oldest and most ambitious biomedical research center in the United States, namely, the Harvard Medical School in Boston, a city of nearly five million inhabitants.

Ubiquitous labyrinths
Gomes came back from Harvard in April 2003 with his wife, Munira Baqui, who was three months pregnant with their daughter at that time. The couple decided to settle in Ribeirão Preto, in the state of São Paulo, he as a recently hired professor, she as a postdoc student at USP. Gomes, one of the few researchers who study the function mechanisms of ubiquitin, was still unwilling to settle down completely and did not refuse to explore unknown terrain. Little by little, he surrounded himself with young researchers such as Adriana Oliveira Manfiolli, Sami Yokoo and Felipe Roberto Teixeira, whose research led to the identification of reservoirs of proteins linked to ubiquitin in the cell nucleus; other more experienced researchers, such as Eduardo Brandt de Oliveira, a biochemist who helped plan and interpret the experiments, and Roy Edward Larson, who worked with two confocal microscopes, were also involved in this work. They are all aware that they work in a highly competitive and complex field of research, especially after the Nobel Prize awarded in 2004: we are currently familiar with no more than a dozen of the 500 to one thousand enzymes that govern ubiquitin activity.