APECED-causing mutations in AIRE reveal the functional domains of the protein
| Autor: | Ismo Ulmanen, Petra Eskelin, Maria Halonen, Jorma J. Palvimo, Jani Saarela, Juha Ollila, Taina Rüppell, Hannele Kangas, Tanja Ilmarinen, Meelis Kolmer, Mauno Vihinen |
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| Rok vydání: | 2004 |
| Předmět: |
Molecular Sequence Data
Mutant Intracellular Space Mutation Missense Biology 03 medical and health sciences Transactivation 0302 clinical medicine Transcription (biology) Chlorocebus aethiops Genetics Animals Humans Missense mutation Amino Acid Sequence Polyendocrinopathies Autoimmune Protein Structure Quaternary Genetics (clinical) 030304 developmental biology Leucine Zippers 0303 health sciences Models Genetic Sequence Homology Amino Acid Chromosome Mapping Autoimmune polyendocrinopathy Subcellular localization Molecular biology Protein Structure Tertiary 3. Good health Models Structural Cytoplasm 030220 oncology & carcinogenesis COS Cells Mutation Trans-Activators Peptides PHD Zinc Fingers Transcription Factors |
| Zdroj: | Human Mutation. 23:245-257 |
| ISSN: | 1098-1004 1059-7794 |
| Popis: | A defective form of the AIRE protein causes autoimmune destruction of target organs by disturbing the immunological tolerance of patients with a rare monogenic disease, autoimmune polyendocrinopathy (APE)-candidiasis (C)-ectodermal dystrophy (ED), APECED. Recently, experiments on knockout mice revealed that AIRE controls autoimmunity by regulating the transcription of peripheral tissue-restricted antigens in thymic medullary epithelial cells. Thus, AIRE provides a unique model for molecular studies of organ-specific autoimmunity. In order to analyze the molecular and cellular consequences of 16 disease-causing mutations in vitro, we studied the subcellular localization, transactivation capacity, homomultimerization, and complex formation of several mutant AIRE polypeptides. Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments. While the PHD zinc fingers were necessary for the transactivation capacity of AIRE, other regions of AIRE also modulated this function. Consequently, most of the mutations decreased transactivation. The HSR domain was responsible for the homomultimerization activity of AIRE; all the missense mutations of the HSR and the SAND domains decreased this activity, but those in other domains did not. The AIRE protein was present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturbed the formation of these complexes. In conclusion, we propose an in vitro model in which AIRE transactivates transcription through heteromeric molecular interactions that are regulated by homomultimerization and conditional localization of AIRE in the nucleus or in the cytoplasm. |
| Databáze: | OpenAIRE |
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