Structural Biochemistry/Proteins/Posttranslational Modification of Protein

Posttranslation modification is the process by which proteome complexity (the global collection of proteins) is built by diversification at both the mRNA level and after translation of mRNAs into proteins by covalent modification of specific proteins. There are two broad categories of posttranslational modifications. The first is the covalent addition of one of more groups, such as phosphoryl, acetyl, or glycosyl, to one or more of the amino acid side chains in a particular protein. The second is the hydrolytic cleavage of one or more peptide bonds in a protein by enzymes called proteases (protein hydolases). There are more the 200 kinds of posttranslational modifications and almost all of them occur by covalent addition of groups to side chains in thousands of proteins carried out by enzymes. These enzymes are proteins with catalytic activity dedicated to effecting the posttranslational modifications. There are many types of catalytic posttranslations, with about 500 proteases encoded in the human genome and over 500 protein kinases for covalent phosphorylations of proteins. Also, there are nearly 150 protein phosphates opposing and balancing the action of protein kinases. Furthermore, there is a small subset of proteins which undergo automodifications- modifications without the help of ancillary catalysts to effect covalent change.

 Scope of Posttranslational Modifications  The diversity of posttranslational modifications by the proteome can be plotted on multiple axis. One scope is the number of proteins modified and thus the number of modified proteins produced. These numbers can differ for a given protein. A second and third axis of scope of posttranslational modification is by the type of amino acid side chain modified and also the type of covalent chemical modification introduced by the posttranslational modification enzymes. In posttranslational modification, the chemical reaction is of enzyme catalyzed transfer of an electrophilic fragment of a co-substrate molecule onto a nucleophilic side chain of the protein undergoing modification. The chemical modification occurs when the attacking nucleophilic side chain of the protein transfers the electrophile. Therefore, common sites for posttranslational modifications are side chains of proteins that can potentially act as nucleophiles.

 Reversible vs. Irreversible Posttranslational Modifications of Proteins  Some posttranslational modifications of proteins are irreversible, due to the nature of the biological function enabled by the modification. The most irreversible modifications are the proteolytic cleavages undergone by all proteins during their life cycles. The removal of N-terminal signal sequences of all proteins passing into the endoplasmic reticulum during the first stage of eukaryotic cell pathways is also irreversible. Also note that some posttranslational modifications are freely reversible in vivo but not in vitro.

Reference: Walsh, Christopher. "Posttranslational Modification of Proteins: Expanding Nature's Inventory." Roberts and Co. (2006): 7-24.