Dumbo may have been ridiculed by his fellow elephants, but his flying skills have been evoked to describe a revolutionary advance in protein science. John Fenn, who received the 2002 Nobel Prize in Chemistry for inventing a technique that makes it possible to study the structure of large, bulky proteins by flying them in the air, said in his prize acceptance speech that his approach provided “wings for molecular elephants.”
Dr. Michal Sharon of the Weizmann Institute’s Biological Chemistry Department is taking this technique a step further: She is providing wings for entire “herds” of molecular elephants. She launches not just individual proteins but entire protein complexes into the air in order to clarify their structure.
The major protein complex that takes flight in her lab is a large molecular machine called the proteasome, whose job in the cell is to break down unwanted proteins. Such recycling is central to a multitude of cellular events, from DNA repair to programmed cell death, while disruptions in proteasome functioning can lead to a host of diseases: Clumps of proteins that have not been properly taken apart can lead to Alzheimer’s and other neurodegenerative diseases. Failure to break down molecules that stimulate cell division can lead to the uncontrolled cell proliferation and growth that occurs in cancer. The improper breakdown of proteins might even trigger a mistaken response from the immune system – for example, in the form of autoimmune disease. Establishing how the proteasome works, then, is essential for understanding and treating numerous diseases.
Sharon’s lab at Weizmann is the first in Israel – and one of only a handful in the world – to study large protein complexes by mass spectroscopy, which provides unique insights into protein structure (see box). Elucidating the proteasome’s structure is an enormous challenge: At least 33 different proteins – a huge assembly of “molecular elephants” – along with additional short-lived protein molecules, interact to create each proteasome.
Sharon is pursuing three major projects. One concerns a proteasome particle called 19S, known as the “brain” because it identifies the proteins to be broken down. During her postdoctoral studies at the University of Cambridge, she already determined part of its structure; now she plans to determine the architecture of the entire “brain,” which includes 18 different subunits. In another project, conducted in collaboration with Profs. Chaim Kahana and Yosef Shaul of Weizmann’s Molecular Genetics Department, Sharon focuses on a second proteasome molecule, called 20S. The scientists are testing the hypothesis that this particle serves as the cell’s “vacuum cleaner,” removing all proteins that are naturally unfolded. In the third project, Sharon investigates the structure of yet another protein complex, the signalosome, whose job is to regulate the placement of special tags on proteins that need to be broken down so that the proteasome’s “brain” can identify them.
These studies are aimed at determining the structure of the proteasome and other biological complexes in minutest detail, a feat that was unthinkable before the advent of the latest technologies. Knowing the structure, in turn, provides valuable information about the way these complexes function in both health and disease.
Mass Spectroscopy in Biology
Mass spectroscopy, whose foundations were laid in 1898, has various uses, from identifying substances to defining their structure. A substance is vaporized into a gas consisting of charged particles, and the properties of these particles are analyzed on the basis of their mass-to-charge ratio. Initially, large biological molecules could not be studied in this manner because they didn’t survive the “bombardment” needed to turn them into a gas. Biologists started using mass spectroscopy to study protein structure only in the 1980s, with the invention of techniques for gently flying proteins in the air, such as John Fenn’s electrospray. Equipment for exploring entire protein complexes, which became available in the late 1990s, is found in only few laboratories around the world, including Sharon’s lab at Weizmann.
In Sharon’s mass spectroscopy machines, microscopic amounts of a protein complex are passed through a thin gold-plated tube and dispersed within a chamber as a spray of charged drops. The technique, referred to as nano-electrospray, allows scientists to study minute quantities of material and analyze non-uniform and asymmetric complexes, which is particularly important for investigating such biological complexes as the proteasome.
Scientist and Mother
Born in Jerusalem, Dr. Michal Sharon earned her Ph.D. from the Weizmann Institute under the guidance of Prof. Jacob Anglister. Her doctoral research focused on the structure of HIV, the virus that causes AIDS. After spending four years as a postdoctoral fellow at the University of Cambridge, she joined the Weizmann staff in the fall of 2007. She is the mother of three: a 9-year-old boy and two girls, aged 7 and 1. Her secret for successfully combining scientific work with motherhood: a strong drive, effective time management and a supportive husband – Alon, whom she met during her army service, when they were both field school instructors in the Negev.
Dr. Michal Sharon’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly; the Chais Family Fellows Program for New Scientists; the Wolfson Family Charitable Trust; Karen Siem, UK; and the estate of Shlomo (Stanislav) and Sabine Bierzwinsky. Dr. Sharon is the incumbent of the Elaine Blond Career Development Chair in Perpetuity.