Endoplasmic Reticulum
In Cell Biology (Third Edition), 2017Protein Folding and Oligomerization in the Endoplasmic Reticulum
Once nascent polypeptides translocate across the ER bilayer through the Sec61 translocon, they emerge into the ER lumen and interact with a wealth of proteins.
Those proteins remove the signal sequence, add oligosaccharides, and direct folding by catalyzing disulfide bond formation and oligomerization.
One such factor, the Hsp70 chaperone BiP, binds unfolded polypeptides by interacting with hydrophobic regions that are normally sequestered in the protein interior (see Fig. 12.12).
These interactions prevent newly synthesized proteins from aggregating
and promote their folding. Cycles of BiP binding also bias the movement
of the polypeptide into the ER lumen but not back out.
Another enzyme called oligosaccharyl transferase adds core sugars to the growing chain when an asparagine in an appropriate sequence context is detected.
A fourth enzyme, protein disulfide isomerase (PDI), catalyzes disulfide exchange between sulfhydryl groups on cysteines allowing the formation of disulfide (S-S) bonds. The oxidizing equivalents to form disulfide bonds flow from flavin adenine dinucleotide (FAD) through two pairs of cysteines of an ER membrane protein
that oxidizes a pair of cysteines in the active site of PDI. PDI then
mediates correct formation of disulfide bonds by forming and breaking
mixed disulfides with polypeptide substrates until the correct
disulfides are formed.
Retention of these folding factors in the ER depends on the sequence lysine–aspartic acid–glutamic acid–leucine (KDEL) at the C-termini of these enzymes. If this sequence is deleted, the mutated protein is transported to the Golgi apparatus and secreted from the cell. Remarkably, addition of KDEL to a normally secreted protein results in its accumulation in the ER.
Folding
and assembly factors interact with proteins throughout their lifetimes
in the ER. The following sections describe the machinery that controls protein folding
and assembly in the ER, mechanisms for sensing correctly folded or
misfolded proteins, and pathways for disposing of misfolded proteins
that accumulate in the ER.
Inga kommentarer:
Skicka en kommentar