Protein Modifications Quiz

Mechanism and Significance of Protein Modifications

• Genetic mutations can lead to mis-targeting of proteins, causing deficiencies and diseases.

• Proteins undergo modifications for activation, including cleavage, hydroxylation, phosphorylation, glycosylation, lipidation, and acetylation.

• Proteins can be targeted to different intracellular sites, including the plasma membrane, cytosol, nucleus, mitochondria, and peroxisome.

• Targeting sequences and modifications aid in proper-folding, stability, and activity of proteins.

• Proteins are placed into two categories based on their synthesis location and targets: Category-1 (synthesized on free ribosomes) and Category-2 (synthesized on rough ER).

• Coupling between ribosomes and rough ER occurs via a signal peptide that binds to the signal recognition particle (SRP).

• Integral membrane proteins require additional signals for crossing and anchoring into the lipid bilayer.

• N-linked glycosylation occurs only in the ER and completes in the Golgi.

• Protein folding is aided by chaperones such as heat shock proteins, which recognize exposed hydrophobic amino acids.

• Quality control mechanisms in the ER allow only correctly folded proteins to move to the Golgi for further modifications.

• Misfolded proteins are degraded in the proteasomes.

• Glucosyl transferase and glucosidase II are involved in recognizing and correcting misfolded proteins.Protein Modifications and Sorting in Golgi Apparatus

• Golgi apparatus is responsible for various types of protein modifications including terminal glycosylation and O-linked glycosylation.

• O-linked glycosylation occurs at the -OH group of selected Ser/Thr amino acids in a primary protein.

• Golgi apparatus also sorts and packages proteins from trans Golgi network and moves them to different targets such as cis Golgi (which receives proteins from ER).

• Lysosomal proteins are sorted by a M6P-receptor and carry mannose-6P (M6P) as a marker.

• M6P receptor (MPR) sorts proteins via clathrin coated vesicles which fuse with endosomes.

• MPR is recycled to the Golgi in a lysosomal pH 4-5 in the early major pathway, and to the PM in a minor pathway which retrieves mannose-6-P.

• ER resident proteins have KDEL sequence at their C-terminal end and are retained by the rER, while some escape to Golgi and are retrieved into rER in a pH-dependent manner.

• Membrane proteins are synthesized as part of the ER membrane and become glycosylated in Golgi, with the glycosylated epitope facing the lumen of ER, Golgi, and vesicle.

• Secretory proteins are exocytosed by default mechanism outside ER, Golgi, and vesicle.

• Defects in protein modifications and sorting can result in mistargeting of proteins or enzymes, leading to diseases such as mucolipidosis II (I-cell disease).

• In I-cell disease, lysosomal enzymes do not carry M6P tag due to a mutated enzyme, resulting in accumulation of mucopolysaccharidoses and inclusion bodies of proteins.

• Inclusion bodies can be seen in the fibroblasts of patients with I-cell disease.