Proteomic analysis and identification of cellular interactors of the giant ubiquitin ligase HERC2

J Proteome Res. 2015 Feb 6;14(2):953-66. doi: 10.1021/pr501005v. Epub 2014 Dec 15.


HERC2 is a large E3 ubiquitin ligase with multiple structural domains that has been implicated in an array of cellular processes. Mutations in HERC2 are linked to developmental delays and impairment caused by nervous system dysfunction, such as Angelman Syndrome and autism-spectrum disorders. However, HERC2 cellular activity and regulation remain poorly understood. We used a broad proteomic approach to survey the landscape of cellular proteins that interact with HERC2. We identified nearly 300 potential interactors, a subset of which we validated binding to HERC2. The potential HERC2 interactors included the eukaryotic translation initiation factor 3 complex, the intracellular transport COPI coatomer complex, the glycogen regulator phosphorylase kinase, beta-catenin, PI3 kinase, and proteins involved in fatty acid transport and iron homeostasis. Through a complex bioinformatic analysis of potential interactors, we linked HERC2 to cellular processes including intracellular protein trafficking and transport, metabolism of cellular energy, and protein translation. Given its size, multidomain structure, and association with various cellular activities, HERC2 may function as a scaffold to integrate protein complexes and bridge critical cellular pathways. This work provides a significant resource with which to interrogate HERC2 function more deeply and evaluate its contributions to mechanisms governing cellular homeostasis and disease.

Keywords: HERC2; UBE3A (E6AP); cellular energy metabolism; eIF3; intracellular transport; translation; translational initiation; vesicle-mediated transport.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Guanine Nucleotide Exchange Factors / analysis
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Protein Interaction Mapping / methods*
  • Proteins / analysis
  • Proteins / metabolism
  • Proteins / physiology
  • Proteome / analysis*
  • Proteome / metabolism*
  • Proteomics
  • Ubiquitin-Protein Ligases


  • Guanine Nucleotide Exchange Factors
  • Proteins
  • Proteome
  • HERC2 protein, human
  • Ubiquitin-Protein Ligases