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Every cell contains about one billion protein molecules that are essential to normal function and, ultimately, to the health of the organism itself. All of these molecules are being recycled constantly — degraded and remade to ensure the cell's well-being.
When a new protein is produced, the molecule migrates within the cell, seeking its correct destination — often in one of about a dozen tightly sealed structures called organelles — where it is needed to carry out a specific task. When this distribution goes awry, normal health and development can be compromised. Many inherited disorders — for example, a rare disease that causes kidney stones at an early age — are caused by targeting errors in proteins.
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An important task of scientists in the next century will be to help in educating and enlightening the public to erase unfounded fears and to highlight the tremendous benefits of science. ”
— Günter Blobel*
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Thus, how these large molecules navigate the maze of the cell and integrate into organelles is a critical question in cell biology. For HHMI investigator Günter Blobel of The Rockefeller University, the quest to understand how proteins navigate and slip through an otherwise impermeable organelle membrane is a central theme of his lab's research program, and work for which he was awarded the 1999 Nobel Prize in Physiology or Medicine.
In 1980, Blobel proposed that signal sequences, or “zip codes,” are built into newly made proteins to direct them to the proper location within the cell. Subsequent work in his laboratory established the existence of this protein distribution system. He found that each newly made protein has an organelle-specific address — its zip code — encoded in its primary structure. Receptors on the surface of an organelle recognize this signal sequence, which is composed of about 10 to 30 amino acids.
Blobel's group also discovered that a protein's signal sequence plays another critical role. In addition to helping proteins find their way around the cell, the sequence triggers the opening of a watery channel on the surface membrane of the organelle, permitting the protein to slip through the membrane and gain access to the organelle where it can play out its role.
For cell biologists, understanding how proteins pass through an otherwise impermeable membrane was akin to biology's version of a ship in a bottle. Protein molecules are large, complicated structures. And while biologists knew that proteins synthesized in a cell's cytoplasm found and gained access to the cell's organelles, they were unsure how the feat was accomplished.
Blobel worked out the details in an organelle known as the endoplasmic reticulum. In their working configurations, proteins are characterized by complicated shapes and folds. To slip through an organelle's membranes, however, they must be unfolded, due tobecause of the small size of the protein-conducting channel. After the a protein passes through, the channel closes but, like a gate, can be opened again for the next protein seeking access to the organelle.
* From Les Prix Nobel, The Nobel Prizes 1999, Editor Tore Frängsmyr, Nobel Foundation, Stockholm, 2000.
Photo: Matthew Septimus
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