Published in:
01-05-2016
Components and Mechanisms of Import, Modification, Folding, and Assembly of Immunoglobulins in the Endoplasmic Reticulum
Author:
Richard Zimmermann
Published in:
Journal of Clinical Immunology
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Special Issue 1/2016
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Abstract
In mammalian cells, the endoplasmic reticulum (ER) plays a central role in biogenesis of secretory- and plasma membrane proteins as well as in cellular calcium (Ca2+) homeostasis. The protein biogenesis function involves an aqueous polypeptide conducting channel in the ER membrane, which is formed by the heterotrimeric Sec61 complex; the store- and receptor-controlled Ca2+- release function requires a steep ER to cytosol gradient, with more than 500 μM free Ca2+ in the ER and 50 nM Ca2+ in the cytosol. Recent work demonstrated that the Sec61 complex can transiently allow passive ER Ca2+ efflux. Therefore, gating of the Sec61 channel has to be tightly regulated by substrates as well as allosteric effectors. The ER lumenal Hsp70-type molecular chaperone, immunoglobulin heavy-chain binding protein (BiP), together with its membrane resident co-chaperone Sec63 facilitates channel opening in a precursor specific manner. In addition, BiP, together with its lumenal co-chaperones, ERj3 and ERj6, as well as cytosolic Ca2+-calmodulin (CaM) in collaboration with the membrane resident Sec62 protein represent allosteric effectors for channel closure. In the course of the last couple of years several human diseases were linked to the Sec61 complex and its effectors and were termed Sec61-channelopathies.