![]() The misfolded proteins inside the ER, however, when accumulated in sufficient concentrations can displace BiP from each of the three proteins. The three proteins in their inactive state bind to the same protein BiP (or GRP78). The second line of defense is the ER-nucleus signaling that involves three proteins PERK, IRE-1, and ATF6 at the ER membrane. The first line of the ER defense is the chaperones inside the ER that attempt to chaperone and correct misfolded proteins. LINES OF DEFENSE FROM THE ENDOPLASMIC RETICULUM This mini-review is also written to review sigma-1 receptors regarding their fundamental action as a molecular chaperone and thus is not meant to be an exhaustive review on sigma-1 receptors as a whole. ![]() The readers can gain more in-depth information on chaperones from several other recent reviews on this subject. The scope of the present review is however to focus on the chaperones inside the ER, in particular a chaperone called the sigma-1 receptor chaperone, and not in any attempt to provide an exhausted overview on chaperones in general. Because the action of chaperones is fundamental to the cell, chaperones are implicated in many diseases including Huntington disease, Parkinsonism, stress disorders, bacterial infection, cystic fibrosis, and cancer. Further, for the similar reason, chaperones are present in almost every species of the living system. Inasmuch as chaperones are important in maintaining the correct conformation of other protein clients and thus conferring their clients' biological activities, chaperones are present not only in the ER but also in the cytosol, mitochondria, and even the extracellular space. The low efficiency, puzzling as it is, makes one wonder if the low efficiency itself may serve for any specific unknown purposes in the living system. Interestingly, the percentage of newly synthesized proteins that are correctly folded and thus are able to exit the ER is pretty low and is usually less than 10%. This task is done either in the form of heteromeric chaperone complexes (co-chaperones) or multiple chaperones coordinated in series. Very often, chaperones inside the ER work in concert with other chaperones to achieve the goal. The correct folding of nascent proteins is performed by chaperone proteins inside the ER. Nascent proteins enter the ER via translocons as linear peptide chains that need to be folded into correct three-dimensional configurations in the ER so that they can exit the ER for further modification and/or transport to reach their final destinations. The endoplasmic reticulum (ER) is the organelle where most of the proteins in the cell are synthesized. Whether the chaperone activity of the sigma-1 receptor attributes to those diseases awaits further investigation. The sigma-1 receptor has been implicated in many diseases including addiction, pain, depression, stroke, and cancer. Thus, the sigma-1 receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress. However, under pathological conditions whereby cells encounter enormous stress that results in the endoplasmic reticulum losing its global Ca 2+ homeostasis, the sigma-1 receptor translocates and counteracts the arising apoptosis. Under physiological conditions, the sigma-1 receptor chaperones the functional IP3 receptor at the endoplasmic reticulum and mitochondrion interface to ensure proper Ca 2+ signaling from endoplasmic reticulum into mitochondrion. The sigma-1 receptor is recently identified as a receptor chaperone whose activity can be activated/deactivated by specific ligands. Chaperones are responsible for certain diseases. Chaperones are proteins that assist the correct folding of other protein clients either when the clients are being synthesized or at their functional localities.
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