Proteins are synthesized as nacent polypeptide chains by the ribosome and must attain their correct three-dimensional shape to perform their specific biological function within the cell. The protein spatial arrangement is meticulously maintained during its functional life time, but after completing its biological task it is then degraded in a timely and efficient manner.
The mammalian cell comprises many thousands of diverse proteins that drive cellular activity all of which must be carefully controlled. A well-balanced proteome, also known as protein homeostasis, requires the coordinated action of a network of molecular chaperones, proteolytic and degradation machineries, together with their regulators, to ensure successful cell function and survival.
Protein homeostasis can be affected by external and endogenous stresses that may upset the balance leading to accumulation of misfolded protein which is toxic for the cell. Therefore, understanding how molecular chaperones and other proteostasis systems operate is of fundamental medical importance, as a failure to maintain protein homeostasis is associated with many diseases including cancer and degenerative disorders.
The endoplasmic reticulum (ER) is a major site for protein folding and maturation within the within the Eukaryotic cell. Proteins that reside within the ER along with proteins destined for the Golgi, plasma membrane, and extra cellular space are synthesized by ribosomes that are attached to the ER membrane. The newly translated polypeptide chain is acted upon by protein folding and post translational modification machinery that include molecular chaperones, glycosylating enzymes and oxidoreductases. The sole ER Hsp 70 chaperone, referred to as BiP, is an abundant protein that plays a major role in protein folding within this compartment. BiP action is influenced by its co-chaperones and other regulators (such as GRP170), which act to stimulate BiP activity - thereby driving protein folding.
The cooperation between chaperones and other post translational modifying enzymes ensure successful preservation of protein structure and therefore its function. We seek to understand - at the molecular level - how these processes regulate protein homeostasis, and how their aberrant function could affect cell fitness.
Unfolded protein response
The ER is also the the first compartment in the secretory pathway and therefore has great significance in specialized secretory cells, such as insulin producing ß cells and antibody producing plasma cells. The sudden requirement to produce secretory proteins exerts pressure on the ability of ER to fold and mature proteins and can create a backlog of misfolded proteins (also known as ER stress) that is toxic for the cell. A rectifying signal is initiated that aims to bolster ER folding capacity to match the burden. This rectifying signal is termed the unfolded protein response (UPR), and the primary component consists of three activator proteins, IRE1, PERK, and ATF6. These activator proteins straddle the ER membrane with regions in both the ER and another cellular compartment, the cytosol. This domain architecture enables the UPR signal to be propagated from one compartment to another within the cell. The UPR detects misfolded proteins and coordinates a transcriptional (nucleus) and translational (cytosolic) response (within the ER). The physiological details of the signaling network are known, but the molecular mechanism, particular of how the signal is detected and then propagated across the ER membrane are not completely understood.