The importance of N186 in the alpha-1-antitrypsin shutter region is revealed by the novel bologna deficiency variant
| Autor: | James A. Irving, Annamaria Fra, Stefania Ottaviani, David A. Lomas, Alice Maria Balderacchi, Emanuela D'Acunto, Elena Miranda, Riccardo Ronzoni, Ilaria Ferrarotti |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
SERPINA1 alleles Alpha-1-antitrypsin deficiency Endoplasmic reticulum Liver storage disease Protein aggregation Serpinopathies Amino Acid Substitution HEK293 Cells Humans Protein Domains alpha 1-Antitrypsin Deficiency Mutation Missense alpha 1-Antitrypsin medicine.medical_treatment medicine.disease_cause 0302 clinical medicine Asparagine Biology (General) Spectroscopy Mutation Alpha 1-antitrypsin deficiency General Medicine Computer Science Applications Chemistry Intracellular congenital hereditary and neonatal diseases and abnormalities QH301-705.5 alpha-1-antitrypsin deficiency endoplasmic reticulum liver storage disease protein aggregation serpinopathies Biology Article Catalysis Inorganic Chemistry 03 medical and health sciences medicine Extracellular Secretion Physical and Theoretical Chemistry Molecular Biology QD1-999 Protease Organic Chemistry medicine.disease Molecular biology 030104 developmental biology 030228 respiratory system Missense |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 5668, p 5668 (2021) International Journal of Molecular Sciences Volume 22 Issue 11 |
| Popis: | Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure. |
| Databáze: | OpenAIRE |
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