Fundamentals of Molecular Biology. Part 1: Molecular Cell Biology - A. N. Ogurtsov 2011

Intracellular Transport of Substances
Three Main Mechanisms of Intracellular Transport

Cellular Membrane Structures play an active role in Intracellular Protein Transport. There are three main mechanisms by which The Cell accomplishes this task (Figure 31).

1. Following synthesis and folding, the protein is delivered in its Native State to the target organelle through specialized membrane pores. This type of delivery is known as gated transport.

2. Transmembrane Translocation of Proteins, during which the polypeptide is first denatured; the polypeptide chain is then threaded through one or more membranes, after which the functional protein refolds.

3. Vesicular trafficking of proteins, during which a vesicle buds off from a membrane, encapsulating the substances to be transported.

Gated transport, for instance, is used to deliver all substances into the Cell Nucleus through nuclear pores. Transmembrane translocation ensures the delivery of Cytosol-synthesized proteins into Peroxisomes, Mitochondria, and METABOLISM/14.html">Chloroplasts. Vesicular trafficking mediates the delivery of substances to Lysosomes and the secretion of molecules from the cell.

Protein addressing is mediated by specific sorting signals embedded within their Structure. Immediately after Protein Synthesis by a ribosome in the cytosol—while the protein is still a simple polypeptide—these sorting signals consist of Amino acid sequences located at the ends of the protein chain, known as targeting sequences.

For proteins synthesized on the membranes of the rough Endoplasmic reticulum, additional sorting signals (such as sugars or phosphate groups) can be added by specialized Enzymes within the cisternae of the Golgi apparatus during Post-translational protein modification.

Such signals typically consist of specific ligands recognized by receptor proteins; these receptor proteins, with the transported proteins attached, in turn bind to the membrane translocation complexes of the respective compartment.

Protein targeting sequences, which comprise chains of 3-80 Amino Acids, are likewise recognized by specialized receptors that deliver the protein to the appropriate translocation complexes. Once delivered to the target compartment, these targeting sequences are usually cleaved from the protein chain by specialized enzymes.

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Figure 31 - Mechanisms of intracellular protein transport

Among the best-characterized targeting sequences are signal Peptides (or signal sequences)—chains of 5-15 predominantly hydrophobic amino acids. The presence of such a signal sequence in a synthesized protein prompts the ribosome to attach to The endoplasmic reticulum, directing the nascent protein chain into the ER lumen rather than the cytosol.

Another example of a targeting sequence is the import signal for proteins destined for Transport from the cytosol into the mitochondrial matrix. This signal is a chain of 20-80 Amino Acids Forming an amphipathic polar a-helix, featuring positively charged amino acids aligned on one side of the helix and hydrophobic amino acids on the other.

For protein targeting to the cell nucleus, a specific sequence of five positively charged amino acids has been identified.

Proteins are targeted to peroxisomes via the peroxisomal targeting sequence Ser-Lys-Lys-COOH, a C-terminal tripeptide.

There are also sorting signals that do not facilitate protein movement; rather, they serve as a retention signal indicating that the protein has reached its final destination and should not be transported any further. For instance, proteins bearing the so-called KDEL sequence (Lys-Asp-Glu-Leu-COOH) at their C-terminus remain in the Endoplasmic reticulum and are prevented from leaving via vesicular transport.

An illustration of the above is calreticulin, a calcium-binding protein of the smooth endoplasmic reticulum (calcium-binding protein of the endoplasmic reticulum - calreticulin), whose Primary Structure is shown in Figure 32.

The first 17 amino acids at the N-terminus of calreticulin act as a signal sequence that initiates protein translocation into the lumen of the endoplasmic reticulum, while the final 4 amino acids—the KDEL sequence—prevent the protein from escaping the reticulum. The Introduction/19.html">Primary structure of the functional protein lies between these two sorting signals.

Figure 32 - Amino Acid Sequence of calreticulin