Ruprecht-Karls-Universitšt Heidelberg

Bernd Bukau
ZMBH Research Group Leader &

DKFZ Division Head

Im Neuenheimer Feld 282
69120 Heidelberg, Germany
Tel.: + 49-6221 54 6795
Fax.: +49-6221 54 5894

Home page at the DKFZ

Welcome to the Bukau Lab!

Biogenesis & quality control of proteins

The ensemble of molecular chaperones are central components of the cellular machinery that establishes and maintains protein homeostasis. Chaperones assist native folding of newly synthesized proteins and repair and eliminate misfolded and aggregated proteins, and therefore have fundamental impact on cell physiology, aging and disease. The goal of our research is to understand the intricate functional network of chaperones and its interplay with proteases in protein biogenesis and quality control, and the molecular working principles of chaperone machines. Furthermore, we want to elucidate causes and consequences of protein aggregation related to disease, in particular neurodegeneration and cancer. As models we are using E. coli, S. cerevisiae, C. elegans and human cells, and we are employing multi-disciplinary approaches ranging from genetics and molecular biology to biochemistry and biophysics. Currently we have three main research themes::

1. Mechanisms of folding and assembly of newly synthesized proteins.
Cells from bacteria to humans have evolved a multilayered machinery that engages translating ribosomes to promote folding and assembly of newly synthesized proteins. Using ribosome profiling, genetics and protein biochemistry, we want to understand how this machinery guides nascent polypeptides to the native state, and how assembly of oligomeric protein complexes is achieved in pro- and eukaryotes.
2. Mechanisms of protein quality control.
Disrupting proteostasis of living cells activates protective quality control systems, which refold or degrade misfolded proteins or sequester potentially cytotoxic misfolded proteins into aggregates, deposited at specific intracellular sites. We want to understand the cellular processes leading to targeted deposition of aggregating proteins inside cells. We are also dissecting the mechanisms by which the Hsp70 chaperone network and the AAA+ disaggregase Hsp104 solubilize and refold aggregated proteins, including disease-associated amyloid fibrils..
3. Propagation of protein misfolding in neurodegenerative diseases (Project group Carmen Nussbaum-Krammer).
Neurodegenerative diseases exhibit a complex pathology involving non-cell autonomous effects and progressive spreading of protein misfolding. Using the metazoan model system C . elegans we want to understand how local protein misfolding is affecting neighboring cells and tissues and how proteostasis is orchestrated at the organismal level.

Selected Publications
Original Papers

Ungelenk, S. et al. Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. (2016) Nat. Commun. 7, 13673 (Abstract).
Schibich, D. et al. Global profiling of SRP interaction with nascent polypeptides. (2016) Nature 536, 219-223, doi: 10.1038/nature19070 (Abstract).
Shieh, Y.-W. et al. Operon structure and cotranslational subunit association direct protein assembly in bacteria. (2015) Science 350, 678 - 680 (Abstract).
Gao, X. et al. Human Hsp70 Disaggregase Reverses Parkinson's-Linked x-Synuclein Amyloid Fibrils. (2015) Mol. Cell. 59, 781-793. doi: 10.1016/j.molcel.2015.07.012 (Abstract).
Nillegoda et al. Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. (2015) Nature 524, 247 - 251, doi:10.1038/nature14884 (read more).
Miller, S.B. et al. Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition. (2015) EMBO J. 34, 778-797. (Abstract)
Carroni, M. et al. Head-to-tail interactions of the coiled-coil domains regulate ClpB activity and cooperation with Hsp70 in protein disaggregation. (2014) Elife doi: 10.7554/eLife.02481 (Abstract).
Sandikci et al. Dynamic enzyme docking to the ribosome coordinates N-terminal processing with polypeptide folding. (2013) Nat. Struct. Mol. Biol. 20, 843-850 (Abstract).
Oguchi et al. A tightly regulated molecular toggle controls AAA+ disaggregase. (2012) Nat. Struct. Mol. Biol. 19, 1338-1346 (Abstract).
Rampelt et al. Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. (2012) EMBO J. 31, 4221-4235 (Abstract).
Hoffmann et al. Concerted action of the ribosome and the associated chaperone trigger factor confines nascent polypeptide folding. (2012) Mol. Cell 48, 63-74 (Abstract).
Oh et al. Selective ribosome profiling reveals the cotranslational chaperone action of trigger factor in vivo. (2011) Cell 147, 1295-1308 (Abstract).
Erbse et al. ClpS is an essential component of the N-end rule pathway in Escherichia coli. (2006) Nature 439, 753-756 (Abstract).
Weibezahn et al. Thermortolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB. (2004) Cell 119, 653-665 (Abstract)
Ferbitz et al. Structure of the trigger factor chaperone in complex with the ribosome defines the molecular environment of the emerging nascent protein chain. (2004) Nature 431, 590-596. (Abstract)
Kramer et al. L23 protein functions as a chaperone docking site on the ribosome. (2002) Nature 419, 171-174 (Abstract)

Mogk et al. Cooperation of Hsp70 and Hsp100 chaperone machines in protein disaggregation. (2015) Front. Mol. Biosci. 2, 22, doi: 10.3389/fmolb.2015.00022. eCollection 2015. (Abstract).
Nillegoda and Bukau. Metazoan Hsp70-based protein disaggregases: emergence and mechanisms. (2015) Front. Mol. Biosci. doi: 10.3389/fmolb.2015.00057. eCollection 2015. (Abstract) .
Gloge et al. Co-translational mechanisms of protein maturation. (2014) Curr. Opin. Struct. Biol. 24, 24-33 (Abstract).
Buchberger et al. Protein quality control in the cytosol and the endoplasmic reticulum: Brothers in arms. (2010) Mol. Cell 40, 238-252 (Abstract)
Tyedmers et al. Cellular strategies for controlling protein aggregation. Nat. Rev. Cell Biol. (2010) 11, 777-788 (Abstract)
Kramer et al. The ribosome as a platform for co-translational processing, folding and targeting of newly synthesized proteins. (2009) Nat. Struct. Mol. Biol. 16, 589-597 (Abstract)
Bukau et al. Getting newly synthesized proteins into shape. (2000) Cell 101, 119-122 (Abstract)