Co-and Posttranslational Modification of Polypeptide Chains

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Chapter: Biochemistry : Protein Synthesis

Many polypeptide chains are covalently modified, either while they are still attached to the ribosome (cotranslational) or after their synthesis has been completed (posttranslational).


Many polypeptide chains are covalently modified, either while they are still attached to the ribosome (cotranslational) or after their synthesis has been completed (posttranslational). These modifications may include removal of part of the translated sequence or the covalent addition of one or more chemical groups required for protein activity. Examples of such modifications are listed below.


A. Trimming

Many proteins destined for secretion from the cell are initially made as large, precursor molecules that are not functionally active. Portions of the protein chain must be removed by specialized endoproteases, resulting in the release of an active molecule. The cellular site of the cleavage reaction depends on the protein to be modified. Some precursor proteins are cleaved in the endoplasmic reticulum or the Golgi apparatus; others are cleaved in developing secretory vesicles (for example, insulin; see Figure 23.4); and still others, such as collagen, are cleaved after secretion.


B. Covalent attachments

Proteins may be activated or inactivated by the covalent attachment of a variety of chemical groups (Figure 31.16). Examples include the following.

Figure 31.16 Covalent modifications of some amino acid residues.


1. Phosphorylation: Phosphorylation occurs on the hydroxyl groups of serine; threonine; or, less frequently, tyrosine residues in a protein. This phosphorylation is catalyzed by one of a family of protein kinases and may be reversed by the action of cellular protein phosphatases. The phosphorylation may increase or decrease the functional activity of the protein. Several examples of phosphorylation reactions have been previously discussed (for example, see Chapter 11, for the regulation of glycogen synthesis and degradation).


2. Glycosylation: Many of the proteins that are destined to become part of a plasma membrane or to be secreted from a cell have carbohydrate chains added en bloc to the amide nitrogen of asparagine (N-linked) or built sequentially on the hydroxyl groups of serine, threonine, or hydroxylysine (O-linked). N-glycosylation occurs in the endoplasmic reticulum and O-glycosyation in the Golgi. (The process of producing such glycoproteins.) Glycosylation is also used to target proteins to the matrix of lysosomes. Lysosomal acid hydrolases are modified by the phosphorylation of mannose residues at carbon 6.


3. Hydroxylation: Proline and lysine residues of the a chains of collagen are extensively hydroxylated by vitamin C–dependent hydroxylases in the endoplasmic reticulum.


4. Other covalent modifications: These may be required for the functional activity of a protein. For example, additional carboxyl groups can be added to glutamate residues by vitamin K–dependent carboxylation. The resulting g-carboxyglutamate (Gla) residues are essential for the activity of several of the blood-clotting proteins. (See Premium Chapter 34.) Biotin is covalently bound to the e-amino groups of lysine residues of biotin-dependent enzymes that catalyze carboxylation reactions such as pyruvate carboxylase. Attachment of lipids, such as farnesyl groups, can help anchor proteins to membranes. Many eukaryotic proteins are cotranslationally acetylated at the N-end. [Note: Reversible acetylation of histone proteins influences gene expression.]


C. Protein folding

Proteins must fold to assume their functional, native state. Folding can be spontaneous (as a result of the primary structure) or facilitated by proteins known as chaperones.


D. Protein degradation

Proteins that are defective (for example, misfolded) or destined for rapid turnover are often marked for destruction by ubiquitination, the attachment of chains of a small, highly conserved protein, called ubiquitin (see Figure 19.3). Proteins marked in this way are rapidly degraded by a cellular component known as the proteasome, which is a macromolecular, ATP-dependent, proteolytic system located in the cytosol. [Note: The DF508 mutation seen in CF causes misfolding of the CFTR protein, resulting in its proteasomal degradation.]

Figure 19.13 Transport of ammonia (NH3) from muscle to the liver. ADP = adenosine diphosphate; Pi = inorganic phosphate; CoA = coenzyme A.

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