Three new Alpha1-Antitrypsin deficiency variants help to define a C-Terminal region regulating conformational change and polymerization

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state

Digital humanism: The time is now

Digital humanism highlights the complex relationships between people, society, nature, and machines. It has been embraced by a growing community of individuals and groups who are setting directions that may change current paradigms. Here we focus on the initiatives generated by the Vienna Manifesto

HEAT SHOCK PROTEINS AND ALCOHOL

In response to many metabolic disturbances and injuries, the cells mount a stress response with the induction of a variety of proteins, most notably the 70 kDa family of heat shock proteins. Included in this family are hsp70 (the inducible form), hsc70 (heat shock cognate, the constitutive form) and grp78 (the constitutively expressed glucoseregulated protein). Alcohol induces injury in diverse tissues and induces the expression of heat shock proteins in different cellular systems. The induction of different members of the hsp70 family reflects specific cellular and molecular aspects of alcohol-induced toxicity. This chapter will cover these studies and the potential mechanisms by which the different members of the hsp70 family may mediate the pathophysiology of organ damage by alcohol

Effects of Amino Acids on Protein Synthesis by Cellular and Subcellular Preparations from Ischaemic Livers

The effects of liver ischaemia on protein synthesis have been studied in tissue slices from ischaemic livers, incubated in vitro. There is a rapid decrease in protein synthesis after the onset of ischaemia, which is more severe in slices than in any cell-free preparation. Liver slices from ischaemic livers do not respond to the presence of a full complement of amino acids with an increase in protein synthesis. The presence of amino acids in the incubation medium does not protect the state of aggregation of the polysomes in the slices from ischaemic livers, as occurs in normal liver slices. Isolated ribosomes, obtained from ischaemic livers and incubated with normal purified factors, show a reduced—but still evident—increase in their protein synthesis in the presence of a full complement of amino acids. This suggests that the decay of cell sap factors also plays a role in the impairment of protein synthesis caused by ischaemia