ER quality control

In collaboration with the MDC laboratories of Thomas Sommer and Erich Wanker we study the structural basis of the ER-associated degradation of misfolded proteins (ERAD) which is promoted by the HRD ubiquitin-ligase complex. Defective proteins are identified in the ER lumen, ubiquitinated and retro-translocated into the cytoplasm by the HRD-ligase complex and ultimately degraded by the proteasome. The lectin Yos9 is important for the recognition of unfolded proteins in the ER lumen by scanning proteins which still expose hydrophobic patches characteristic for incompletely folded molecules for mature surface carbo­hydrate structures. Crystal structure analysis showed Yos9 to adopt a dimeric protein struc­ture which likely reflects a dimeric structure of the entire HRD-ligase complex. Evidence for this HRD-ligase dimer was earlier presented when it was shown that the cytosolic subunit Usa1 of the HRD ligase also promoted dimerization. Another protein involved in ERAD is the AAA ATPase p97 (Cdc48 in yeast) whose interaction with regulatory ligands we also study by protein crystallography.

Structure of the dimerization domain of Yos9