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Tuesday, September 25, 2007

The Signal Hypothesis

Monday's Molecule #44 is signal recognition particle or SRP. The figure is a model of SRP (red) bound to a ribosome at the exit site of the tunnel in the large subunit (white asterisk) (Schaffitzel et al. 2006). In the right-hand version of the model you can see that SRP is made up of an RNA molecule and associated proteins.

Signal recognition particle is an important component of the secretory pathway. The mechanism of secretion in response to a signal on the growing polypeptide is known as the Signal Hypothesis. Here's how we describe it in our textbook Principles of Biochemistry 4/e.
Secreted proteins are synthesized on the surface of the endoplasmic reticulum, and the newly synthesized protein is passed through the membrane into the lumen. In cells that make large amounts of secreted protein, the endoplasmic reticulum membranes are covered with ribosomes.

The clue to the process by which many proteins cross the membrane of the endoplasmic reticulum appears in the first 20 or so residues of the nascent polypeptide chain. In most membrane-bound and secreted proteins, these residues are present only in the nascent polypeptide, not in the mature protein. The N-terminal sequence of residues that is proteolytically removed from the protein precursor is called the signal peptide since it is the portion of the precursor that signals the protein to cross a membrane. Signal peptides vary in length and composition, but they are typically from 16 to 30 residues long and include 4 to 15 hydrophobic residues.

In eukaryotes, many proteins destined for secretion appear to be translocated across the endoplasmic reticulum by the pathway shown in the Figure. In the first step, an 80S initiation complex—including a ribosome, a Met-tRNAiMet molecule, and an mRNA molecule—forms in the cytosol. Next, the ribosome begins translating the mRNA and synthesizing the signal peptide at the N-terminus of the precursor. Once the signal peptide has been synthesized and extruded from the ribosome, it binds to a protein-RNA complex called a signal recognition particle (SRP).

SRP is a small ribonucleoprotein containing a 300-nucleotide RNA molecule called 7SL RNA and four proteins. SRP recognizes and binds to the signal peptide as it emerges from the ribosome. When SRP binds, further translation is blocked. The SRP-ribosome complex then binds to an SRP receptor protein (also known as docking protein) on the cytosolic face of the endoplasmic reticulum. The ribosome is anchored to the membrane of the endoplasmic reticulum by ribosome-binding proteins called ribophorins, and the signal peptide is inserted into the membrane at a pore that is part of the complex formed by the endoplasmic reticulum proteins at the docking site.

Once the ribosome-SRP complex is bound to the membrane, the inhibition of translation is relieved and SRP dissociates in a reaction coupled to GTP hydrolysis. Thus, the role of SRP is to recognize nascent polypeptides containing a signal peptide and to target the translation complex to the surface of the endoplasmic reticulum.

Once the translation complex is bound to the membrane, translation resumes and the new polypeptide chain passes through the membrane. The signal peptide is then cleaved from the nascent polypeptide by a signal peptidase, an integral membrane protein associated with the pore complex. The transport of proteins across the membrane is assisted by chaperones in the lumen of the endoplasmic reticulum. In addition to their role in protein folding, chaperones are required for translocation, and their activity requires ATP hydrolysis. When protein synthesis terminates, the ribosome dissociates from the endoplasmic reticulum, and the translation complex disassembles.
©:L.A. Moran and Pearson/Prentice Hall

Horton, H.R., Moran, L.A., Scrimgeour, K.G., Perry, M.D. and Rawn, J.D. (2006) Principles of Biochemistry, 4th edition. Pearson Prentice Hall, Upper Saddle River NJ (USA)

Schaffitzel, C., Oswald, M., Berger, I., Ishikawa, T., Abrahams, J.P., Koerten, H.K., Koning, R.I. and Ban, N. (2006) Structure of the E. coli signal recognition particle bound to a translating ribosome. Nature 444:503-506.


Torbjörn Larsson said...
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Torbjörn Larsson said...

Another fascinating science post. (I might soon have to pick up a modern biochemistry text, damn you!)

I naively thought spatial separation by secretion was less energy demanding than active pumping across a membrane, but perhaps it can't cheat the concentration difference it works against. Still having trouble thinking like a chemist here...