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Multivalency regulates activity in an intrinsically disordered transcription factor

S. Clark, JB. Myers, A. King, R. Fiala, J. Novacek, G. Pearce, J. Heierhorst, SL. Reichow, EJ. Barbar,

. 2018 ; 7 (-) : . [pub] 20180501

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19035274

Grantová podpora
R35GM124779 NIGMS NIH HHS - United States
S10 OD018518 NIH HHS - United States
R35 GM124779 NIGMS NIH HHS - United States
R01-084276 NIGMS NIH HHS - United States
R01 GM084276 NIGMS NIH HHS - United States
1S10OD018518 NIH HHS - United States

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.

Citace poskytuje Crossref.org

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$a The transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays, we developed a model that proposes a concerted role of intrinsic disorder and multiple LC8 binding events in regulating LC8 transcription. We demonstrate that the long intrinsically disordered C-terminal domain of ASCIZ binds LC8 to form a dynamic ensemble of complexes with a gradient of transcriptional activity that is inversely proportional to LC8 occupancy. The preference for low occupancy complexes at saturating LC8 concentrations with both human and Drosophila ASCIZ indicates that negative cooperativity is an important feature of ASCIZ-LC8 interactions. The prevalence of intrinsic disorder and multivalency among transcription factors suggests that formation of heterogeneous, dynamic complexes is a widespread mechanism for tuning transcriptional regulation.
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$a Myers, Janette B $u Department of Chemistry, Portland State University, Oregon, United States.
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$a King, Ashleigh $u St. Vincent's Institute of Medical Research, The University of Melbourne, Victoria, Australia. Department of Medicine, St. Vincent's Health, The University of Melbourne, Victoria, Australia.
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$a Fiala, Radovan $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
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$a Novacek, Jiri $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
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$a Pearce, Grant $u School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
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$a Heierhorst, Jörg $u St. Vincent's Institute of Medical Research, The University of Melbourne, Victoria, Australia. Department of Medicine, St. Vincent's Health, The University of Melbourne, Victoria, Australia.
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$a Reichow, Steve L $u Department of Chemistry, Portland State University, Oregon, United States.
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