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

Abstract

The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca2+) 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 Ca2+ 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 Ca2+ 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 Ca2+. 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 Ca2+-permeable channel, the closed complex is impermeable even to Ca2+. 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 Ca2+-permeability.

Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases

“…The best-understood role of the ER is to synthesise and insert proteins into the ER membrane or lumen, and this happens primarily by ribosomes associating with the cytosolic face of the ER, where the newly synthesised polypeptide chain is translocated through the Sec61 translocon, as reviewed in this special issue by Sicking et al [ 48 ]. In S. Cerevisiae , sheet ribosome density was found to be significantly larger than tubule ribosome density [ 49 ].…”

Inhibitors of the Sec61 Complex and Novel High Throughput Screening Strategies to Target the Protein Translocation Pathway

“…The correct translocation of proteins is crucial for the proper functioning of cells. In fact, inefficient protein translocation has been linked to many liver, kidney, and metabolic diseases [ 36 , 90 ]. Cancer cells, on the other hand, depend heavily on efficient protein translocation into the ER to support their fast growth.…”

“…Novel small molecule inhibitors of protein translocation at the Sec61 complex may be important innovations in pharmacology and may have several medicinal indications in the future. From the previous section, it is clear that Sec61 inhibitors act by a selective or non-selective mechanism of action [ 39 , 90 ].…”

“…Broad-spectrum or non-selective inhibitors impair translocation of many or even all proteins targeted to the Sec61 complex [ 39 , 90 ]. They may represent novel cancer drugs slowing down tumor cell growth.…”

Molecular Modeling of Signal Peptide Recognition by Eukaryotic Sec Complexes

“…Furthermore, it was found that different human hereditary and tumour diseases are associated with Sec61 channel gating [ 6 ]. Interestingly, various human genetic diseases result from single point mutations in the SPs of certain precursor polypeptides [ 6 , 7 , 8 ].…”