Rapoport Proves Existence of Molecule

A Harvard researcher last month uncovered an elusive molecule thought to be the key to all normal cell function.

Tom A. Rapoport, professor of cell biology at the Medical School, last month unveiled the first-ever picture of the molecule, which is essential to protein trafficking and secretion in cells of organisms ranging from bacteria to mammals.

The existence of the molecule was first postulated about 20 years ago, and scientists were continually collecting evidence pointing toward its existence, but not until Rapoport's findings did anyone verify the molecule's existence.

"The channel had been postulated to exist, but there was no experimental evidence. So for the first time we can actually see the channel in the membrane that allows proteins to go across," Rapoport said in an interview last night.

"The key to the study is the fact that we can isolate the channel component, that is, the membrane protein complex that forms the channel," he said.

Proteins need to cross membranes to travel from their site of production to their final destinations, but the purpose of the membranes is to prevent molecules like proteins from passing through.

Thus, this discovery--made in collaboration with a group at Boston University headed by Christopher Akeys and a group at Brown University headed by Ken Miller--finally explains how proteins manage to cross their membranes.

Rapoport said his interest in the subject began more than 20 years ago when he was studying preinsulin, a precursor of the hormone insulin.

He found that preinsulin had another precursor, prepreinsulin, which like other proteins has a signal sequence that triggers secretion or transport across the membrane.

"I wanted to know how this signal works and how the protein gets across a membrane that normally presents a barrier to macro-molecules," Rapoport said.

Now that researchers have proven the existence of the elusive channel, Rapoport said they will continue studying it to find how it works.

"The existence or demonstration of the existence of the channel does not tell us how it works, that is, how is it opened and closed," Rapoport said. "How do proteins move across in one direction and how does it open laterally to let membrane proteins out into the lipid bilayer?"

In a study published in this week's Nature, Rapoport explains that the channel can transport proteins in two directions.

"The channel can be used to transport proteins backwards from the endoplasmic reticulum into the cytosol, which is, of course the retrograde direction of what proteins would normally do," Rapoport said.

This finding is significant, he said, because it shows how a virus can evade the body's attempt to kill it.

"[The study] shows that viruses can trick the immune system by preventing molecules from getting to the surface that the cell needs to fight the virus," Rapoport said.

The Nature study was done in collaboration with Hidde Ploegh at MIT.