Now he and others, including Schekman, are sussing out that machinery. Schekman suspected that, by studying how peroxisomes form at the ER, he could uncover a mechanism by which cells move material around in vesicles. Over the years, his team had helped characterize the cell's best-known secretion pathway, known as the SEC pathway, by which the ER packages proteins into vesicles for shipment to the Golgi apparatus, which processes them and directs them to the cell membrane to move out of the cell. Evidence suggested that peroxisomes are formed through a different mechanism, Schekman says. For example, mutations that block normal ER protein secretion don't affect ER-derived peroxisome production.

To deduce how the ER produces peroxisomes, Schekman's team has created a yeast cell extract that can, in a test tube, produce vesicles that may be peroxisome precursors. They are fishing around in the extract to find the partner proteins that work with Pex19 to get the ER to produce vesicles that form peroxisomes. “Until now people thought there was one avenue of egress from the ER to the Golgi apparatus for secretion. Now it's clear that the ER feeds the growth of other organelles in the cells—certainly the peroxisome and I bet others.”

The work should shed light on how individual membrane proteins are directed to different destinations in the cell, Schekman says. “That underlies how the eukaryotic cell achieves its compartmental design.” Compartmental design allows several complex biochemical reactions to take place at the same time, a phenomenon that makes higher forms of life possible.

Throughout the 1990s, Kunau and others identified cellular workhorse proteins that the peroxisome needs to function and probed how they worked together. Peroxisomes look like water balloons, with a lipid membrane and a watery interior; some proteins are embedded in the membrane, while others float inside. Every mutation that caused human peroxisomal disease blocked one protein or another from getting into the peroxisome, and two-thirds of them blocked proteins from reaching the organelle's interior, Valle says. Over the past decade, Suresh Subramani of the University of California, San Diego, and his colleagues have uncovered a novel molecular machine that imports those proteins. That, in turn, has reshaped biologists' thinking about how cells direct enzymes and other types of proteins to the correct cellular organelle.

Proteins do not enter peroxisomes the same way they enter other organelles. Before being imported into mitochondria, for example, or the light-harvesting chloroplasts in plants, or the ER, a protein must unfold from its three-dimensional conformation into a long string of amino acids, which is then threaded through the organelle's membrane into its interior. But in peroxisomes, proteins move through the membrane in their folded, three-dimensional state, often escorted by partner proteins. In a series of studies that began in the mid-1990s, Subramani and his colleagues figured out how Pex5, a peroxisomal receptor in the cytoplasm, grabs a protein, escorts it through an entry gate in a large protein complex in the peroxisome's membrane, drops it off inside, and then returns to the cytoplasm through a separate exit to begin the process anew. However, receptors can get stuck in the exit gate, shutting down the entire import process, Subramani explains.

Recently, Subramani's team uncovered the RADAR pathway, an enzymatic pathway that marks receptors that are blocking the exit door and then uses proteasomes, one of the cell's “garbage disposals,” to mark the receptors, destroy them, and restart the import process. “It would be fascinating to know how the cell senses and activates the garbage disposal when it's needed,” Subramani says. These and other studies could shed light on how cells regulate how many of each type of organelle they keep around. Answers to that question could yield clues to how muscle cells maintain more mitochondria than other cells to supply them with extra energy, or how regulation of organelle number goes awry to cause disease.

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