Zip Code plan for proteins wins Nobel.

Don't forget the Zip Code! That's a rule fixed in the minds of most people because they know their mail probably won't be delivered without this number.

The realization that the billion or so proteins within a cell bear molecular Zip Codes that direct them to appropriate destinations has won German-born cell biologist Gunter Blobel this year's Nobel Prize in Physiology or Medicine.

Besides revealing a fundamental method by which cells organize themselves and carry out functions, Blobel's work has helped explain several rare diseases in which proteins travel to the wrong location. In their efforts to engineer plants and bacteria to synthesize drugs or other proteins, biotech companies have also made use of the molecular zip codes within proteins.

Blobel, a Howard Hughes Medical Institute investigator at Rockefeller University in New York, made his Nobel-winning discoveries in the 1970s. The original observation occurred when he was examining protein synthesis and the role of a ribbonlike compartment within the cell known as the endoplasmic reticulum.

This structure serves as a processing station for many proteins under construction, modifying the molecules before sending them elsewhere in the cell or placing them into the secretory pathway that will release them. Blobel noticed that a protein that normally moves through the endoplasmic reticulum was slightly bigger when it was made without the aid of that compartment.

From that observation, he speculated that extra amino acids on the larger protein act as a signal, subsequently removed, that direct it into the compartment. A series of experiments confirmed that premise and revealed a transport molecule that ferries proteins bearing the signal to the endoplasmic reticulum.

Inspired by those findings, Blobel developed his signal hypothesis, which holds that all newly minted proteins contain an amino acid string that determines their eventual home. Blobel and other scientists have since identified many such signals, including ones that guide proteins to mitochondria, the nucleus, and other locations.

"It's one of the early hypotheses in cell biology that really stood the test of time with very few modifications. It was visionary," says Danny J. Schnell of Rutgers University in Newark, N.J., who studied protein trafficking under Blobel.

Investigators are still trying to comprehend how cells use a protein's Zip Code to distribute the molecule. Schnell compares the uncertainty to knowing that envelopes must bear a zip code but not understanding how the postal service picks up, sorts, and delivers the mail.

Misplacing a protein is more serious than losing a letter, however. "There are diseases where proteins are mistargeted in cells," says Tom A. Rapoport of Harvard Medical School in Boston, who investigates how proteins directed to the endoplasmic reticulum cross its membrane.

In one condition characterized by frequent kidney stones, for example, mutations in the Zip Code cause a protein normally destined for a cell compartment called a peroxisome to end up in mitochondria. In another rare illness, cells mistakenly secrete enzymes instead of storing them in sacs called lysosomes.

So far, Blobel's work has not led to ways to correct such misplacements, but scientists have attached secretory Zip Codes to proteins that they plan to produce in yeast, bacteria, or plants. With this strategy, the researchers can engineer the cells to secrete valuable drugs or enzymes.