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.

Highlights

  • The ribosome-studded or rough endoplasmic reticulum (ER) of nucleated human cells plays essential roles in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction (Figure 1) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]

  • Cleavable signal peptides (SPs) are removed from the inserting or incoming precursor polypeptides by yet another heteromultimeric enzyme, the signal peptidase complex (SPC) [91,92]

  • There is redundancy in these three targeting systems and they can substitute for each other as a backup at least to a certain extent. Another general lesson is that not all aminoterminal SPs and transmembrane helices (TMHs), which are involved in ER targeting and import of precursor polypeptides, were created equal, i.e., some have special requirements, which is not surprising considering the large variety of precursor polypeptides (Figure 4)

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Summary

Introduction

The ribosome-studded or rough endoplasmic reticulum (ER) of nucleated human cells plays essential roles in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction (Figure 1) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]. Sec gating to the open state is not solely facilitated by its substrates, the amino-terminal signal peptides (SPs) or transmembrane helices (TMHs) of precursor polypeptides [70,71,72,73,74,75], it is supported by ribosomes in co-translational transport [52,55] and/or by several Sec interaction partners, such as translocon-associated protein or TRAP complex [53,56,76,77] and Sec62/Sec complex in cooperation with BiP [69,78,79,80,81], respectively The latter are defined as allosteric effectors of the channel since they interact with the complex at sites, which are distinct from the precursor binding sites. We discuss the human hereditary and tumor diseases as well as human pathogens that are linked to Sec channel gating, the Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or Ca2+ permeability of the ER membrane and highlight the importance of the functionality of the system [86]

The Human Sec61 Translocon
Entry of Precursor Polypeptides into the ER
Targeting of Precursor Polypeptides to the ER
Structure of the Sec61 Complex
Dynamics of the Sec61 Complex
Auxiliary Factors of the Sec61 Complex
Allosteric Effectors of the Sec61 Channel for Channel Opening
Additional Auxiliary Factors of the Sec61 Complex
Structural Considerations
Gating of the Sec61 Channel by BiP
Structure and Dynamics of BiP
Bacterial and Fungal Toxins That Target the Sec61 Channel
Mutated Variants of the Sec61 Channel
Findings
Tumor Diseases That Are Related to the Sec61 Channel
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