Protein targeting

Protein targeting a.k.a. protein sorting includes the mechanisms by which a biological cell transports proteins to the appropriate organelle for insertion into a membrane or secretion to the outside. (This article deals with protein targeting in eukaryotes except as noted.)

Protein translocation

In 1970, Günter Blobel conducted experiments on the translocation of proteins across membranes. He was awarded the 1999 Nobel prize for his findings. He discovered that many proteins have a signal sequence, that is, a short amino acid sequence at one end that functions like a postal code for the target organelle. The translation of mRNA into protein by a ribosome takes place within the cytosol. If the synthesized proteins "belong" in a different organelle, they can be transported there in either of two ways, depending on the protein.

Cotranslational translocation

The N-terminal signal sequence of the protein is recognized by a signal recognition particle (SRP) while the protein is still being synthesized on the ribosome. The synthesis pauses while the ribosome-protein complex is transferred to an SRP receptor on the endoplasmic reticulum (ER, which is a membrane-bound organelle). There, the nascent protein is inserted into the Sec61 translocation complex (also known as the translocon) that passes through the ER membrane. The signal sequence is immediately cleaved from the polypeptide once it has been translocated into the ER by signal peptidase in secretory proteins. This signal sequence processing differs for some ER transmembrane proteins. Within the ER, the protein is first covered by a chaperone protein to protect it from the high concentration of other proteins in the ER, giving it time to fold correctly. Once folded, the protein is modified as needed (for example, by glycosylation), then transported to the Golgi apparatus for further processing and goes to its target organelles or is retained in the ER by various ER retention mechanisms.

Posttranslational translocation

Even though most proteins are cotranslationally translocated, some are translated in the cytosol and later transported to their destination. This occurs for proteins that go to a mitochondrion, a chloroplast, or a peroxisome (proteins that go to the latter have their signal sequence at the C terminus). Also, proteins targeted for the nucleus are translocated post-translation. They pass through the nuclear envelope via nuclear pores.

Transmembrane proteins

The amino acid chain of transmembrane proteins, which often are transmembrane receptors, passes through a membrane one or several times. They are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor sequence.

Sorting of proteins to mitochondria

Most mitochondrial proteins are synthesized as cytosolic precursors containing uptake peptide signals.

Mitochondrial matrix targeting sequences are rich in positively charged amino acids and hydroxylated ones.

Proteins are targeted to submitochondrial compartments by multiple signals and several pathways.

Targeting to the outer membrane, intermembrane space, and inner membrane often requires another signal sequence in addition to the matrix targeting sequence.

Cytosolic chaperones deliver proteins to channel linked receptors in the mitochondrial membrane.

Sorting of proteins to peroxisomes

All peroxisomal proteins are encoded by nuclear genes.

The signal for uptake into the peroxisomal matrix is SKL (serine-lysine-leucine).

Diseases

Peroxisomal protein transport is defective in the following genetic diseases:

Zellweger syndrome.
Adrenoleukodystrophy (ADR).

Receptor-mediated endocytosis

Several molecules that attach to special receptors called coated pits on the outside of cells cause the cell to perform endocytosis, an invagination of the plasma membrane to incorporate the molecule and associated structures into endosomes. This mechanism is used for three main purposes:

Uptake of essential metabolites, for example, LDL.
Uptake of some hormones and growth factors, for example, epidermal growth factor and nerve growth factor.
Uptake of proteins that are to be destroyed, for example, antigens in phagocytotic cells like macrophages.

Receptor-mediated endocytosis can also be "abused":

Some viruses, for example, the Semliki forest virus, enter the cell through this mechanism.
Cholera and diphtheria toxins also enter the cell this way.

Protein destruction

Defective proteins are occasionally produced, or they may be damaged later, for example, by oxidative stress. Damaged proteins can be recycled. Proteins can have very different half lives, mainly depending on their N-terminal amino acid residue. The recycling mechanism is mediated by ubiquitin.