Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase

Scientific Reports
Zhaofeng YeCarlos J Camacho

Abstract

C-terminus of Hsc/p70-Interacting Protein (CHIP) is a homodimeric E3 ubiquitin ligase. Each CHIP monomer consists of a tetratricopeptide-repeat (TPR), helix-turn-helix (HH), and U-box domain. In contrast to nearly all homodimeric proteins, CHIP is asymmetric. To uncover the origins of asymmetry, we performed molecular dynamics simulations of dimer assembly. We determined that a CHIP monomer is most stable when the HH domain has an extended helix that supports intra-monomer TPR-U-box interaction, blocking the E2-binding surface of the U-box. We also discovered that monomers first dimerize symmetrically through their HH domains, which then triggers U-box dimerization. This brings the extended helices into close proximity, including a repulsive stretch of positively charged residues. Unable to smoothly unwind, this conflict bends the helices until the helix of one protomer breaks to relieve the repulsion. The abrupt snapping of the helix forces the C-terminal residues of the other protomer to disrupt that protomer's TPR-U-box tight binding interface, swiftly exposing and activating one of the E2 binding sites. Mutagenesis and biochemical experiments confirm that C-terminal residues are necessary both to maintain CHIP stability and...Continue Reading

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Citations

Oct 10, 2019·American Journal of Respiratory Cell and Molecular Biology·Khalequz ZamanBenjamin Gaston
Mar 27, 2019·Scientific Reports·Lucía Quintana-GallardoJosé María Valpuesta
Jul 6, 2020·Analytical Biochemistry·Samuel K Estabrooks, Jeffrey L Brodsky
Apr 19, 2019·The Journal of Physical Chemistry. B·Baofu QiaoMonica Olvera de la Cruz

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Methods Mentioned

BETA
MDS
ubiquitination
circular dichroism

Software Mentioned

PBSA

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