Structural basis of diversity and homodimerization specificity of zinc-finger-associated domains in Drosophila
| Autor: | Vladimir Popov, Alena Yu. Nikolaeva, Artem Bonchuk, Anna Fedotova, Konstantin M. Boyko, Pavel Georgiev, Sofya V. Lushchekina, Anastasia Khrustaleva |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular AcademicSubjects/SCI00010 Mutagenesis (molecular biology technique) Computational biology Biology Crystallography X-Ray DNA-binding protein Homology (biology) Structural Biology CYS2-HIS2 Zinc Fingers Genetics Animals Drosophila Proteins Genomic organization Zinc finger chemistry.chemical_classification Zinc Fingers biology.organism_classification Amino acid DNA-Binding Proteins Drosophila melanogaster chemistry Mutagenesis Drosophila Protein Multimerization Dimerization Transcription Factors |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | In arthropods, zinc finger-associated domains (ZADs) are found at the N-termini of many DNA-binding proteins with tandem arrays of Cys2-His2 zinc fingers (ZAD-C2H2 proteins). ZAD-C2H2 proteins undergo fast evolutionary lineage-specific expansion and functional diversification. Here, we show that all ZADs from Drosophila melanogaster form homodimers, but only certain ZADs with high homology can also heterodimerize. CG2712, for example, is unable to heterodimerize with its paralog, the previously characterized insulator protein Zw5, with which it shares 46% homology. We obtained a crystal structure of CG2712 protein's ZAD domain that, in spite of a low sequence homology, has similar spatial organization with the only known ZAD structure (from Grauzone protein). Steric clashes prevented the formation of heterodimers between Grauzone and CG2712 ZADs. Using detailed structural analysis, site-directed mutagenesis, and molecular dynamics simulations, we demonstrated that rapid evolutionary acquisition of interaction specificity was mediated by the more energy-favorable formation of homodimers in comparison to heterodimers, and that this specificity was achieved by multiple amino acid substitutions resulting in the formation or breaking of stabilizing interactions. We speculate that specific homodimerization of ZAD-C2H2 proteins is important for their architectural role in genome organization. |
| Databáze: | OpenAIRE |
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