Mechanical Properties of Chaperone BiP, the Master Regulator of the Endoplasmic Reticulum

Abstract

Immunoglobulin heavy-chain-binding protein (BiP protein) is a 75-kDa Hsp70 monomeric ATPase motor that plays broad and crucial roles maintaining proteostasis inside the cell. Its malfunction has been related with the appearance of many and important health problems such as neurodegenerative diseases, cancer, and heart diseases, among others. In particular, it is involved in many endoplasmic reticulum (ER) processes and functions, such as protein synthesis, folding, and assembly, and also it works in the posttranslational mechanism of protein translocation. However, it is unknown what kind of molecular motor BiP works like, since the mechanochemical mechanism that BiP utilizes to perform its work during posttranslational translocation across the ER is not fully understood. One novel approach to study both structural and catalytic properties of BiP considers that the viscoelastic regime behavior of the enzymes (considering them as a spring) and their mechanical properties are correlated with catalysis and ligand binding. Structurally, BiP is formed by two domains, and to establish a correlation between BiP structure and catalysis and how its conformational and viscoelastic changes are coupled to ligand binding, catalysis, and allosterism (information transmitted between the domains), optical tweezers and nano-rheology techniques have been essential in this regard.

α-Mangostin Promotes In Vitro and In Vivo Degradation of Androgen Receptor and AR-V7 Splice Variant in Prostate Cancer Cells

“…Through immunoprecipitation assays, we observed that α-mangostin promoted an interaction between AR and BiP ( Figure 4 C) and that this interaction was also promoted in 22Rν1 cells treated with α-mangostin that had been transfected with exogenous BiP that contained a His-GST tag ( Figure 4 D). As BiP is a cell stress and chaperone protein, we hypothesize that α-mangostin increases the expression of BiP, which then associates with AR and chaperones it to the proteasome for ubiquitination and degradation [ 62 ]. Our previous data showed that there was no change in the expression of UPR proteins after α-mangostin treatments in primary prostate epithelial cells from PCa patients, indicating that this unique protein-protein interaction only occurs in PCa cells and only when they are treated with α-mangostin [ 23 ].…”

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

“…For the translocation of the last amino acid residues that remain in the ribosomal exit tunnel when translation is completed, proteins rely on the binding immunoglobin protein (BiP), a lumenal translocation chaperone. BiP acts as a molecular ratchet by binding to the preprotein and pulling it toward the ER lumen to complete translocation in an ATP dependent manner [ 80 , 81 , 82 , 83 ]. Once translocated, the proteins are post-translationally modified in the ER lumen.…”

“…The orthologous bacterial SecYEG complex translocates proteins across the prokaryotic plasma membrane, therefore, inhibitors of the SecYEG complex may represent novel antibiotics that are urgently needed. A proof of principle for SecYEG inhibition was published, for example, decatransin [ 99 ] and eeyarestatin [ 81 ], although these compounds inhibit both the eukaryotic Sec61 complex and prokaryotic SecYEG.…”

The Stress of Lung Aging: Endoplasmic Reticulum and Senescence Tête-à-Tête

“…The BiP-ATP complex has an increased binding capacity for low affinity substrates including IRE1, PERK, and ATF6 and maintains them in an inactivated state under nonstress conditions (17). The accumulation of unfolded or misfolded proteins in the ER lumen leads to the dissociation of BiP-ATP from ER stress markers and hydrolyzation of ATP by BiP ATPase domain to BiP-ADP complex, which binds to hydrophobic peptides contained in the unfolded proteins (40,43). Thus the dissociation of BiP-ATP from ER stress markers results in activation of UPR signaling pathways, establishing BiP as the principal regulator of ER stress (40,43).…”

“…The accumulation of unfolded or misfolded proteins in the ER lumen leads to the dissociation of BiP-ATP from ER stress markers and hydrolyzation of ATP by BiP ATPase domain to BiP-ADP complex, which binds to hydrophobic peptides contained in the unfolded proteins (40,43). Thus the dissociation of BiP-ATP from ER stress markers results in activation of UPR signaling pathways, establishing BiP as the principal regulator of ER stress (40,43). IRE1 and PERK are activated through autophosphorylation of their cytosolic serine/threonine kinase domains, while ATF6 is first translocated to the Golgi apparatus where it is cleaved in the luminal domain and the phospholipid bilayer by site-1 protease (S1P) and metalloprotease site-2 protease (S2P), respectively (40,44,45).…”