Molecular ‘ZIP coding’ system speeds proteins to their appointed destinations

From brain receptors to hormones, nearly half of the proteins in the body serve to transport biochemical information from one cell to another. Yale researchers have now described a major component of the molecular machinery for reading the “ZIP code” that guides a protein’s movement from the inside to the outside of the cells. The findings open up a new window on evolution and offer possible novel targets for drug discovery.

In a cover story in the February 18 issue of Science, the study revealed the molecular details of the machinery that identifies and delivers proteins to their correct destination. A protein first must be identified for transport, then find the right target and, finally, be transported through cellular membranes to its destination. Under the direction of Jennifer A. Doudna, Ph.D., professor of molecular biophysics and biochemistry and an associate investigator of the Howard Hughes Medical Institute, co-investigator Robert Batey, Ph.D., determined the atomic structure of the protein-RNA complex that recognizes an amino acid ZIP code tag, or signaling sequence, that identifies proteins to be transported to the cell membrane for secretion.

This complex, part of the signal recognition particle, or SRP, was already known to serve a recognition function, but the discovery suggested a previously unknown and surprising role for RNA in the direct recognition of the amino acid ZIP code, or signal peptide, in the protein being identified for transport. “We think that the RNA and the protein in the SRP work together to recognize the signal peptide,” Doudna said. “Previously it’s been thought that the functions of the proteins and the RNA were separate. Here we are seeing an example of true molecular collusion.”