Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 5; p. 1036
• Main Authors: Sicking, Mark, Lang, Sven, Bochen, Florian, Roos, Andreas, Drenth, Joost P H, Zakaria, Muhammad, Zimmermann, Richard, Linxweiler, Maximilian
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-04-2021; MDPI
• Subjects: Allosteric properties; Allosteric Regulation; Apoptosis; Binding sites; Biosynthesis; BiP; Calcium (intracellular); Calcium homeostasis; Calcium permeability; Calcium signalling; Channel gating; Channelopathies - metabolism; Channelopathies - physiopathology; Chaperones; common variable immunodeficiency; congenital disorder of glycosylation; Cytosol; Endoplasmic reticulum; Endoplasmic Reticulum Chaperone BiP; Enzymes; Heat-Shock Proteins - metabolism; Homeostasis; Hsp70 protein; Humans; Ion Channel Gating; Membrane permeability; Neoplasms - metabolism; Neoplasms - pathology; neutropenia; polycystic liver disease; Polypeptides; Protein folding; Protein transport; Proteins; Review; SEC Translocation Channels - metabolism; Signal transduction; SSR/TRAP complex; congenital disorder of glycosylation; Sec61-channelopathies; BiP; neutropenia; common variable immunodeficiency; Sec62; polycystic liver disease; endoplasmic reticulum; Sec63
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10051036

The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca
) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca
ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca
homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca
. The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca
-permeable channel, the closed complex is impermeable even to Ca
. Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca
-permeability.