Structural and biochemical basis of Yos9 protein dimerization and possible contribution to self-association of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation ubiquitin-ligase complex

J Biol Chem. 2012 Mar 9;287(11):8633-40. doi: 10.1074/jbc.M111.317644. Epub 2012 Jan 18.


In yeast, the membrane-bound HMG-CoA reductase degradation (HRD) ubiquitin-ligase complex is a key player of the ER-associated protein degradation pathway that targets misfolded proteins for proteolysis. Yos9, a component of the luminal submodule of the ligase, scans proteins for specific oligosaccharide modifications, which constitute a critical determinant of the degradation signal. Here, we report the crystal structure of the Yos9 domain that was previously suggested to confer binding to Hrd3, another component of the HRD complex. We observe an αβ-roll domain architecture and a dimeric assembly which are confirmed by analytical ultracentrifugation of both the crystallized domain and full-length Yos9. Our binding studies indicate that, instead of this domain, the N-terminal part of Yos9 including the mannose 6-phosphate receptor homology domain mediates the association with Hrd3 in vitro. Our results support the model of a dimeric state of the HRD complex and provide first-time evidence of self-association on its luminal side.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Crystallography, X-Ray
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Hydroxymethylglutaryl CoA Reductases / chemistry*
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Models, Molecular*
  • Multienzyme Complexes / chemistry*
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism
  • Protein Multimerization*
  • Protein Structure, Tertiary
  • Proteolysis
  • Saccharomyces cerevisiae / chemistry*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Ubiquitin-Protein Ligases / chemistry*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Unfolded Protein Response / physiology


  • Carrier Proteins
  • Multienzyme Complexes
  • Saccharomyces cerevisiae Proteins
  • Yos9 protein, S cerevisiae
  • Hydroxymethylglutaryl CoA Reductases
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/2YMA