Protein folding in the ER is facilitated by protein chaperones, such as the Hsp70 family member BiP, and PTMs, such as asparagine(N) linked-glycosylation and disulfide bond formation.74 Folding begins cotranslationally and is enhanced by folding catalysts. For example, the proper pairing and formation of disulfide bonds is catalyzed by oxidoreductases, such as protein disulfide isomerase (PDI), that also shuffle nonnative disulfide bonds. In contrast to the highly reducing environment of the cytosol where disulfide bonds do not typically form, the lumen of the ER is highly oxidizing so that disulfide bond formation is favored.

Most proteins that enter the secretory pathway are modified by N-glycosylation which starts with the transfer of a core oligosaccharide from a lipid-linked dolichol donor to an asparagine residue within the consensus sequence N-X-S/T of a nascent polypeptide (X can be any amino acid except for proline). The N-linked oligosaccharide is composed of a glucose3-mannose9-N-acetylglucosamine2 unit (Glc3 Man9 GlcNac2 ) and is transferred to the asparagine residue by an ER oligosaccharyltransferase (OST). Further processing of the terminal sugars occurs in the ER and after the polypeptide transits the Golgi compartment. Many blood proteins (e.g., immunoglobulins, anti-proteases, and coagulation factors) and many membrane proteins are glycosylated. The human A, B, and O blood-group system is defined by distinct glycosyltransferases. Both the A and B antigens are similar to the O antigen but contain additional residues: the A antigen contains an additional N-acetylgalactosamine, and the B antigen an extra galactose residue attached to the outer galactose. People with the O antigen carry antibodies against A and B, whereas people with the A or B antigen carry anti-B or anti-A antibodies, respectively, determining blood transfusion compatibility. The hormone erythropoietin requires a particular, complex type of N-glycan chains for its biologic function to stimulate erythropoiesis in vivo: recombinant erythropoietin that lacks its normal N-linked oligosaccharides when injected into humans is much less potent than the normal protein because it is degraded much faster than the endogenous, glycosylated protein. Thus glycans protect proteins from protease digestion and heat denaturation, confer hydrophilicity and adhesive properties, mediate protein-protein inter actions, and promote protein folding and trafficking.

The ER is also the site of γ-carboxylation of glutamic acid residues (e.g., in the coagulation factors II, VII, IX, and X as described earlier and as detailed in Box 1). Another modification is the attachment of a GPI anchor to the C-terminal end of proteins with concomitant release of the GPI signal peptide. The GPI attachment promotes membrane association.

Box1. Human Glycosylation Disorders

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مواضيع ذات صلة

How AraC Protein Loops and Unloops

DNA Looping and Repression of araBAD

Binding Sites of the ara Regulatory Proteins

Endoplasmic Reticulum-Associated Degradation and the Unfolded Protein Response

Protein Modifications

Regulating AraC Synthesis

Repression by AraC

Detection and Isolation of AraC Protein

Genetics of the Arabinose System

The Eukaryotic Genome

Nucleic Acids and Their Organization in Eukaryotic, Prokaryotic, and Viral Genomes

The Sugar Arabinose and Arabinose Metabolism