Research Report 2010 - MDC

Structure of the GroupGroup LeaderDr. Thomas SommerScientistsDr. Christian HirschDr. Ernst JaroschDr. Birgit MeusserThomas SommerMechanisms of Protein Quality ControlThe endoplasmic reticulum (ER) is a cellular organelle through which a significant proportionof proteins pass on their way to their functional sites in membranes, exocytic and endocyticcompartments, or the cell exterior. Far from being a passive traffic way, the ER is home to anarray of molecular chaperones, which help proteins to fold and guide their maturation. Despitethis support, protein biogenesis is an error-prone process. A considerable fraction of all newlysynthesized polypeptides fail to attain their native conformation due to mutations,transcriptional and translational errors, folding defects, or imbalanced subunit synthesis.Mature proteins can be damaged by environmental stress conditions, such as high-energyradiation, chemical insults, or metabolic by-products. Malfunction or aggregation of defectiveproteins challenges the homeostasis of the ER and the cell as a whole. As a consequence,evolution has produced a protein quality control (PQC) network that operates on several levelsto maintain the integrity of the ER.The work of this group focuses on how the ER proteinquality control system selectively disposes aberrantproteins without jeopardizing nascent polypeptidesthat also populate this compartment. Current data suggestthat polypeptides are initially protected fromdegradation by a specific N-linked glycan structure toallow their maturation. Later, ER mannosidases generatea unique glycan code that flags potentially misfoldedsubstrates. This signal is decoded by an ubiquitin ligaseanchored in the ER membrane. Proteins committedfor degradation are transported across the ER membranein a process termed protein dislocation.Subsequently, substrate molecules are ubiquitylatedand degraded by the 26S proteasome. This process isreferred to as ER associated degradation or ERAD. Butmisfolded proteins are not the only substrates of thissystem. It also regulates sterol synthesis by eliminatingthe pathway’s rate-limiting enzyme when sterols areabundantly available. This example shows that ERADalso has a regulatory component that may not be limitedto this anabolic pathway.Since the ERAD pathway appears to be conserved fromyeast to mammals, we use the model organismSaccharomyces cerevisiae to investigate the fundamentalmechanisms and to identify the key components ofthis important pathway. These are the HRD ubiquitinligase and the Doa10 ubiquitin ligase. The HRD-ligase iscrucial for turnover of membrane-bound (ERAD-M) andER-luminal substrates (ERAD-L). Doa10 targets membraneproteins for degradation that carry lesions intheir cytoplasmic domains (ERAD-C). Both yeast ubiquitinligases and their co-factors that have been identifiedso far are summarized in Fig. 1. The mammaliancounterparts of the yeast components are mentionedas well.Usa1 Functions as a Scaffold of the HRD-ligaseSabine Horn, Ernst Jarosch, Christian Hirsch in collaborationwith Jennifer Hanna, Anja Schütz, and Udo HeinemannThe multiprotein HRD-ligase (HMG-CoA ReductaseDegradation) singles out terminally misfolded proteinsof the ER and routes them for degradation to cytoplas-102 Cancer Research