FAD-linked presenilin-1 mutants impede translation regulation under ER stress

FAD mutations in presenilin-1 (PS1) cause attenuation of the induction of the endoplasmic reticulum (ER)-resident chaperone GRP78/BiP under ER stress, due to disturbed function of IRE1, the sensor for accumulation of unfolded protein in the ER lumen. PERK, an ER-resident transmembrane protein kinase, is also a sensor for the unfolded protein response (UPR), causing phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) to inhibit translation initiation. Here, we report that the FAD mutant PS1 disturbs the UPR by attenuating both the activation of PERK and the phosphorylation of eIF2alpha. Consistent with the results of a disturbed UPR, inhibition of protein synthesis under ER stress was impaired in cells expressing PS1 mutants. These results suggest that mutant PS1 impedes general translational attenuation regulated by PERK and eIF2alpha, resulting in an increased load of newly synthesized proteins into the ER and subsequently increasing vulnerability to ER stress.     

Polynomial algebra reveals diverging roles of the unfolded protein response in endothelial cells during ischemia–reperfusion injury

The unfolded protein response (UPR) – the endoplasmic reticulum stress response – is found in various pathologies including ischemia–reperfusion injury (IRI). However, its role during IRI is still unclear. Here, by combining two different bioinformatical methods – a method based on ordinary differential equations (Time Series Network Inference) and an algebraic method (probabilistic polynomial dynamical systems) – we identified the IRE1α–XBP1 and the ATF6 pathways as the main UPR effectors involved in cell’s adaptation to IRI. We validated these findings experimentally by assessing the impact of their knock-out and knock-down on cell survival during IRI.     

Synaptopodin family of natively unfolded, actin binding proteins: physical properties and potential biological functions

The synaptopodin family of proteins consists of at least 3 members: synaptopodin, the synaptopodin 2 proteins, and the synaptopodin 2-like proteins. Each family member has at least 3 isoforms that are produced by alternative splicing. Synaptopodin family members are basic proteins that are rich in proline and have little regular 2° or 3° structure at physiological temperature, pH and ionic strength. Like other natively unfolded proteins, synaptopodin family members have multiple binding partners including actin and other actin-binding proteins. Several members of the synaptopodin family have been shown to stimulate actin polymerization and to bundle actin filaments either on their own or in collaboration with other proteins. Synaptopodin 2 has been shown to accelerate nucleation of actin filament formation and to induce actin bundling. The actin polymerization activity is inhibited by Ca²⁺-calmodulin. Synaptopodin 2 proteins are localized in Z-bands of striated and heart muscle and dense bodies of smooth muscle cells. Depending on the developmental status and stress, at least one member of the synaptopodin family can occupy nuclei of some cells. Members of the synaptopodin 2 subfamily have been implicated in cancers.     

Selective estrogen-induced apoptosis in breast cancer

Antihormone therapy remains the gold standard of care in the treatment of estrogen receptor (ER) positive breast cancer. However, development of acquired long term antihormone resistance exposes a vulnerability to estrogen that induces apoptosis. Laboratory and clinical studies indicate that successful therapy with estrogens is dependent on the duration of estrogen withdrawal and menopausal status of a woman. Interrogation of estradiol (E₂) induced apoptosis using molecular studies indicate treatment of long term estrogen deprived MCF-7 breast cancer cells with estrogen causes an endoplasmic reticulum stress response that induces an unfolded protein response signal to inhibit protein translation. E₂ binds to the ER and mediates apoptosis through the classical genomic pathway. Furthermore, the induction of apoptosis by estrogens is dependent on the conformation of the estrogen–ER complex. In this review, we explore the mechanism and the processes involved in the paradox of estrogen induced apoptosis and the new selectivity of estrogen action on different cell populations that is correctly been deciphered for clinical practice.     

Unfolding the complexities of ER chaperones in health and disease: report on the 11th international calreticulin workshop

The 11th International Calreticulin workshop was held May 15–18, 2015 at New York University School of Medicine-Langone Medical Center, New York. The meeting highlighted many of the new discoveries in the past 2 years involving the important role of molecular chaperones in physiological and pathological processes. Crucial to the understanding of these disease processes was the role of chaperones in maintaining quality control of protein processing in the endoplasmic reticulum, the importance of Ca² regulation acting through its action in stress-related diseases, and the trafficking of glycoproteins to the cell surface. Central to maintaining healthy cell physiology is the correct ER-associated protein degradation of specific misfolded proteins. Information on different mechanisms involved in the degradation of misfolded proteins was revealed. This was a landmark meeting for the chaperone field in terms of new insights into their roles in physiology. These insights included the unfolded protein response, innate/adaptive immunity, tissue repair, the functions of calreticulin/chaperones from the cell surface, and extracellular environment. Diseases included neurodegenerative disorders, prion disease, autoimmunity, fibrosis-related disease, the host immune response to cancer, and hematologic diseases associated with calreticulin mutations. The 12th calreticulin workshop is planned for the spring of 2017 in Delphi, Greece.     

Abstracts: Albany 2007, The 15th Conversation

Abstract

Forty nine molecular dynamics simulations of unfolding trajectories of the segment B1 of streptococcal protein G (GB1) provide a direct demonstration of the diversity of unfolding pathway and give a statistically utmost unfolding pathway under the physical property space. Twelve physical properties of the protein were chosen to construct a 12-dimensional property space. Then the 12-dimentional property space was reduced to a 3-dimentional principle component property space. Under the property space, the multiple unfolding trajectories look like “trees”, which have some common characters. The “root of the tree” corresponds to the native state, the “bole” homologizes the partially unfolded conformations, and the “crown” is in correspondence to the unfolded state. These unfolding trajectories can be divided into three types. The first one has the characters of straight “bole” and “crown” corresponding to a fast two-state unfolding pathway of GB1. The second one has the character of “the standstill in the middle tree bole”, which may correspond to a three-state unfolding pathway. The third one has the character of “the circuitous bole” corresponding to a slow two-state unfolding pathway. The fast two-state unfolding pathway is a statistically utmost unfolding pathway or preferred pathway of GB1, which occupies 53% of 49 unfolding trajectories. In the property space all the unfolding trajectories construct a thermal unfolding pathway ensemble of GB1. The unfolding pathway ensemble resembles a funnel that is gradually emanative from the native state ensemble to the unfolded state ensemble. In the property space, the thermal unfolded state distribution looks like electronic cloud in quantum mechanics. The unfolded states of the independent unfolding simulation trajectories have substantial overlaps, indicating that the thermal unfolded states are confined by the physical property values, and the number of protein unfolded state are much less than that was believed before.