A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery.

Abstract	The cullin 4-DNA-damage-binding protein 1 (CUL4-DDB1) ubiquitin ligase machinery regulates diverse cellular functions and can be subverted by pathogenic viruses. Here we report the crystal structure of DDB1 in complex with a central fragment of hepatitis B virus X protein (HBx), whose DDB1-binding activity is important for viral infection. The structure reveals that HBx binds DDB1 through an alpha-helical motif, which is also found in the unrelated paramyxovirus SV5-V protein despite their sequence divergence. Our structure-based functional analysis suggests that, like SV5-V, HBx captures DDB1 to redirect the ubiquitin ligase activity of the CUL4-DDB1 E3 ligase. We also identify the alpha-helical motif shared by these viral proteins in the cellular substrate-recruiting subunits of the E3 complex, the DDB1-CUL4-associated factors (DCAFs) that are functionally mimicked by the viral hijackers. Together, our studies reveal a common yet promiscuous structural element that is important for the assembly of cellular and virally hijacked CUL4-DDB1 E3 complexes.
Authors	Ti Li, Eva I Robert, Pieter C van Breugel, Michel Strubin, Ning Zheng
Journal	Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 17 Issue 1 Pg. 105-11 (Jan 2010) ISSN: 1545-9985 [Electronic] United States
PMID	19966799 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	CUL4A protein, human Cullin Proteins DDB1 protein, human DNA-Binding Proteins Trans-Activators Viral Regulatory and Accessory Proteins hepatitis B virus X protein Green Fluorescent Proteins Luciferases Ubiquitin-Protein Ligases
Topics	Blotting, Western Colony-Forming Units Assay Crystallization Cullin Proteins (metabolism) DNA-Binding Proteins (chemistry, metabolism) Green Fluorescent Proteins HeLa Cells Humans Immunoprecipitation Luciferases Models, Molecular Protein Binding Protein Structure, Secondary Trans-Activators (chemistry, metabolism) Two-Hybrid System Techniques Ubiquitin-Protein Ligases (metabolism) Viral Regulatory and Accessory Proteins

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