Control mechanisms governing protein folding

Biološka funkcija proteina uvelike ovisi o njihovoj konformaciji, stoga je proces smatanja kojim proteini poprimaju pravilnu trodimenzionalnu strukturu iznimno vaţan i kontroliran u stanici. Smatanje je potpomognuto molekularnim šaperonima koji stupaju u interakciju s novosintetiziranim proteinima. Endoplazmatski retikulum (ER) vaţan je organel u kojem se smata i doraĎuje gotovo trećina staničnih proteina. Ukoliko je njegova homeostaza narušena dolazi do nakupljanja nesmotanih proteina i stanja poznatog kao stres endoplazmatskog retikuluma. Posljedično dolazi do aktivacije odgovora na nesmotane proteine (UPR), staničnog obrambenog mehanizma koji nastoji smanjiti količinu nesmotanih proteina u ER-u. ProvoĎenje signala inducirano je senzornim proteinima smještenima u membrani ER-a. Kod kvasca je to protein Ire1, a kod Metazoa IRE1, PERK i ATF6. Rezultat signalne kaskade je povećana transkripcija gena čiji su produkti uključeni u smatanje proteina i sintezu membrane ER-a, ali i smanjenje sinteze staničnih proteina. UPR regulira i proces degradacije povezane s endoplazmatskim retikulumom (ERAD) za proteine koji ne mogu biti pravilno smotani. Ispravno funkcioniranje navedenih mehanizama vaţno je za organizam budući da nakupljanje nesmotanih proteina i formiranje proteinskih agregata moţe uzrokovati mnoge bolesti.Biological function of proteins largely depends on their conformation, therefore the folding process by which proteins arrange in a proper three-dimensional structure is extremely important and controlled in the cell. Folding is assisted by molecular chaperones that interact with newly synthesized proteins. The endoplasmic reticulum (ER) is an important organelle in which almost a third of cellular proteins are folded and modified. If ER homeostasis is disturbed, unfolded proteins accumulate in its lumen leading to a condition known as endoplasmic reticulum stress. As a result, a cellular defense mechanism known as the unfolded protein response (UPR) is activated. UPR strives to reduce the content of unfolded proteins in the ER. Signal transduction is induced by sensory proteins located in the ER membrane. Ire1 is present in yeast, and proteins IRE1, PERK and ATF6 are present in Metazoans. The result of the signaling cascade is increased transcription of genes whose products are involved in protein folding and ER membrane synthesis, and also reduction of global protein synthesis. If protein cannot be properly folded, it is degraded by the process called endoplasmic reticulum-associated protein degradation (ERAD) which is also regulated by the UPR. Proper functioning of these mechanisms is important for the organism since the accumulation of unfolded proteins and formation of protein aggregates can cause various diseases