4.7 Article

The Structure of the ZMYND8/Drebrin Complex Suggests a Cytoplasmic Sequestering Mechanism of ZMYND8 by Drebrin

Journal

STRUCTURE
Volume 25, Issue 11, Pages 1657-+

Publisher

CELL PRESS
DOI: 10.1016/j.str.2017.08.014

Keywords

-

Funding

  1. National Basic Research Program of China [2014CB910204]
  2. Minister of Science and Technology of China [2016YFA0501903]
  3. Natural Science Foundation of Guangdong Province [2016A030312016]
  4. Shenzhen Basic Research grant [JCYJ20160229153100269]
  5. RGC of Hong Kong [16103614, 16149516, AoE-M09-12]
  6. National Natural Science Foundation of China [31400647, 31670765]
  7. Shenzhen Basic Research grants [JCYJ20160427185712266, JCYJ20170411090807530]

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Malfunctions of the actin binding protein Drebrin have been implicated in various human diseases such as Alzheimer's disease, cognitive impairments, cancer, and digestive disorders, though with poorly understood mechanisms. The ADF-H domain of Drebrin does not contain actin binding and depolymerizing activity. Instead, it binds to a histone marker reader, ZMYND8. Here we present the high-resolution crystal structure of Drebrin ADF-H in complex with the ZMYND8 PHD-BROMO-PWWP tandem, elucidating the mechanistic basis governing the highly specific interaction of the two proteins. The structure reveals that the ZMYND8 PHD-BROMO-PWWP tandem forms a structural supramodule that is necessary for binding to Drebrin ADF-H. Drebrin ADF-H competes with modified histone for binding to ZMYND8. Binding of Drebrin can shuttle ZMYND8 from nucleus to cytoplasm in living cells. Taken together, our study uncovers a non-actin target binding mode for ADF-H domains, and suggests that Drebrin may regulate activities of epigenetic reader ZMYND8 via its cytoplasmic sequestration.

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