Multivalency regulates activity in an intrinsically disordered transcription factor
The transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays,...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/36258 |
| _version_ | 1811199372348620800 |
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| author | Sarah Clark Janette B Myers Ashleigh King Radovan Fiala Jiri Novacek Grant Pearce Jörg Heierhorst Steve L Reichow Elisar J Barbar |
| author_facet | Sarah Clark Janette B Myers Ashleigh King Radovan Fiala Jiri Novacek Grant Pearce Jörg Heierhorst Steve L Reichow Elisar J Barbar |
| author_sort | Sarah Clark |
| collection | DOAJ |
| description | The transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays, we developed a model that proposes a concerted role of intrinsic disorder and multiple LC8 binding events in regulating LC8 transcription. We demonstrate that the long intrinsically disordered C-terminal domain of ASCIZ binds LC8 to form a dynamic ensemble of complexes with a gradient of transcriptional activity that is inversely proportional to LC8 occupancy. The preference for low occupancy complexes at saturating LC8 concentrations with both human and Drosophila ASCIZ indicates that negative cooperativity is an important feature of ASCIZ-LC8 interactions. The prevalence of intrinsic disorder and multivalency among transcription factors suggests that formation of heterogeneous, dynamic complexes is a widespread mechanism for tuning transcriptional regulation. |
| first_indexed | 2024-04-12T01:47:11Z |
| format | Article |
| id | doaj.art-444a811f37fb46c798f96e99e116678e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:47:11Z |
| publishDate | 2018-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-444a811f37fb46c798f96e99e116678e2022-12-22T03:53:02ZengeLife Sciences Publications LtdeLife2050-084X2018-05-01710.7554/eLife.36258Multivalency regulates activity in an intrinsically disordered transcription factorSarah Clark0Janette B Myers1https://orcid.org/0000-0002-7758-2649Ashleigh King2Radovan Fiala3Jiri Novacek4Grant Pearce5https://orcid.org/0000-0002-2683-0331Jörg Heierhorst6https://orcid.org/0000-0003-2789-9514Steve L Reichow7Elisar J Barbar8https://orcid.org/0000-0003-4892-5259Department of Biochemistry and Biophysics, Oregon State University, Oregon, United StatesDepartment of Chemistry, Portland State University, Oregon, United StatesSt. Vincent’s Institute of Medical Research, The University of Melbourne, Victoria, Australia; Department of Medicine, St. Vincent’s Health, The University of Melbourne, Victoria, AustraliaCentral European Institute of Technology, Masaryk University, Brno, Czech RepublicCentral European Institute of Technology, Masaryk University, Brno, Czech RepublicSchool of Biological Sciences, University of Canterbury, Christchurch, New ZealandSt. Vincent’s Institute of Medical Research, The University of Melbourne, Victoria, Australia; Department of Medicine, St. Vincent’s Health, The University of Melbourne, Victoria, AustraliaDepartment of Chemistry, Portland State University, Oregon, United StatesDepartment of Biochemistry and Biophysics, Oregon State University, Oregon, United StatesThe transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays, we developed a model that proposes a concerted role of intrinsic disorder and multiple LC8 binding events in regulating LC8 transcription. We demonstrate that the long intrinsically disordered C-terminal domain of ASCIZ binds LC8 to form a dynamic ensemble of complexes with a gradient of transcriptional activity that is inversely proportional to LC8 occupancy. The preference for low occupancy complexes at saturating LC8 concentrations with both human and Drosophila ASCIZ indicates that negative cooperativity is an important feature of ASCIZ-LC8 interactions. The prevalence of intrinsic disorder and multivalency among transcription factors suggests that formation of heterogeneous, dynamic complexes is a widespread mechanism for tuning transcriptional regulation.https://elifesciences.org/articles/36258transcription factorsIntrinsically disordered proteinselectron microscopymultivalencydynamic complexesNMR |
| spellingShingle | Sarah Clark Janette B Myers Ashleigh King Radovan Fiala Jiri Novacek Grant Pearce Jörg Heierhorst Steve L Reichow Elisar J Barbar Multivalency regulates activity in an intrinsically disordered transcription factor eLife transcription factors Intrinsically disordered proteins electron microscopy multivalency dynamic complexes NMR |
| title | Multivalency regulates activity in an intrinsically disordered transcription factor |
| title_full | Multivalency regulates activity in an intrinsically disordered transcription factor |
| title_fullStr | Multivalency regulates activity in an intrinsically disordered transcription factor |
| title_full_unstemmed | Multivalency regulates activity in an intrinsically disordered transcription factor |
| title_short | Multivalency regulates activity in an intrinsically disordered transcription factor |
| title_sort | multivalency regulates activity in an intrinsically disordered transcription factor |
| topic | transcription factors Intrinsically disordered proteins electron microscopy multivalency dynamic complexes NMR |
| url | https://elifesciences.org/articles/36258 |
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