In the cell, as in vitro, the final conformation of a protein is determined by its amino-acid sequence. But whereas some isolated proteins can be denatured and refolded in vitro in the absence of other macromolecular cellular components, folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.

Protein folding in the cell.

The folding of many newly synthesized proteins in the cell depends on a set of conserved proteins known as molecular chaperones. These prevent the formation of misfolded protein structures, both under normal conditions and when cells are exposed to stresses such as high temperature. Significant progress has been made in the understanding of the ATP-dependent mechanisms used by the Hsp70 and chaperonin families of molecular chaperones, which can cooperate to assist in folding new polypeptide chains.

Molecular chaperones in cellular protein folding.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

/pdf/a-sars-cov-2-protein-interaction-map-reveals-targets-for-5d1m2n6hc1.pdf

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Efficient folding of many newly synthesized proteins depends on assistance from molecular chaperones, which serve to prevent protein misfolding and aggregation in the crowded environment of the cell. Nascent chain–binding chaperones, including trigger factor, Hsp70, and prefoldin, stabilize elongating chains on ribosomes in a nonaggregated state. Folding in the cytosol is achieved either on controlled chain release from these factors or after transfer of newly synthesized proteins to downstream chaperones, such as the chaperonins. These are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. Understanding how the thousands of different proteins synthesized in a cell use this chaperone machinery has profound implications for biotechnology and medicine.

https://science.sciencemag.org/content/sci/295/5561/1852.full.pdf

Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein

'Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada 2Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI, USA, 3Department of Genetics, Yale University, New Haven, CT, USA 4 Physiological Chemistry Institute, University of Munich, Munich, Germany 'GSF Clinical Hematology Institute, Munich, Germany 6 Department of Pharmacology, University of Nebraska Medical Center, Omaha, NE, USA 7Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA

Molecular chaperones in biology and medicine at Obernai.

IND02-05 The NeuroDeRisk toolbox: DeRisking chemical structures for neurotoxic adverse outcomes

/pdf/understanding-base-excess-be-merits-and-pitfalls-qxh832u7.pdf

Understanding base excess (BE): merits and pitfalls

1H, 13C and 15N Backbone Resonance Assignment of the Hsp90 Binding Domain of Human Cdc37

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2892%2980653-X

Thomas Langer

Papers

Molecular chaperones in biology and medicine at Obernai.

IND02-05 The NeuroDeRisk toolbox: DeRisking chemical structures for neurotoxic adverse outcomes

Understanding base excess (BE): merits and pitfalls

1H, 13C and 15N Backbone Resonance Assignment of the Hsp90 Binding Domain of Human Cdc37

Formation and quantification of protein complexes between peroxisomal alcohol oxidase and GroEL.