TitleMultivalency regulates activity in an intrinsically disordered transcription factor.
Publication TypeJournal Article
Year of Publication2018
AuthorsClark S, Myers JB, King A, Fiala R, Novacek J, Pearce G, Heierhorst J, Reichow SL, Barbar EJ
JournalElife
Volume7
Date Published2018 May 01
ISSN2050-084X
Abstract

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 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.

DOI10.7554/eLife.36258
Alternate JournalElife
PubMed ID29714690
PubMed Central IDPMC5963919
Grant ListOperational Infrastructure Support / / Victorian State Government /
APP1022469 / / National Health and Medical Research Council /
R35GM124779 / / National Institute of General Medical Sciences /
Impact Award / / College of Science at Oregon State University /
S10 OD018518 / OD / NIH HHS / United States
APP1026125 / / National Health and Medical Research Council /
R35 GM124779 / GM / NIGMS NIH HHS / United States
R01-084276 / / National Institute of General Medical Sciences /
R01 GM084276 / GM / NIGMS NIH HHS / United States
1S10OD018518 / / National Institutes of Health /