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.
Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy. fra@med.unibs.it
Anna M
AM
Fra
Bibek
B
Gooptu
Ilaria
I
Ferrarotti
Elena
E
Miranda
Roberta
R
Scabini
Riccardo
R
Ronzoni
Federica
F
Benini
Luciano
L
Corda
Daniela
D
Medicina
Maurizio
M
Luisetti
Luisa
L
Schiaffonati
D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D020033:Protein Isoforms; D055503:Protein Multimerization / Q000235:genetics*; D016415:Sequence Alignment; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000737:chemistry* / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000378:metabolism*
D020033:Protein Isoforms; D000515:alpha 1-Antitrypsin