MPI of Biochemistry identifies mechanism that provides crucial knowledge for the treatment of neurodegenerative diseases
Prof. Dr. F.-Ulrich Hartl and Dr. Manajit Hayer-Hartl ensured the maintenance of proteaostasis in E. coli with limited available chaperones
© Magdalena Jooss @ MPI für Biochemie & Susanne Vondenbusch-Teetz @ MPI für Biochemie
Prof. Dr. F.-Ulrich Hartl, Director “Cellular Biochemistry” at Max Planck Institute of Biochemistry (left). Dr. Manajit Hayer-Hartl, Group Leader “Chaperonin-assisted Protein Folding” at Max Planck Institute of Biochemistry (right).
“We are excited about these findings, which describe a new mechanism of protein quality control at the bacterial ribosome. It will be interesting whether a similar system exists in eukaryotic cells.”
Prof. Dr. F.-Ulrich Hartl
Director at Max Planck Institute of Biochemistry
Frau Dr. Manajit Hayer-Hartl
Group Leader at Max Planck Institute of Biochemistry
Researchers at the Max Planck Institute of Biochemistry (MPIB) have identified a novel mechanism that ensures proteostasis maintenance in E. coli when chaperone availability is limited. Chaperones ensure the correct folding of proteins. But what happens if the chaperone network is defective? F.-Ulrich Hartl, Manajit Hayer-Hartl and their team have characterized the ribosome-associated chaperone network in Escherichia coli. For the first time, they discovered that a defect in this network results in a response at the ribosome. The release factor RF3 is recruited to the ribosome and then mediates the termination of misfolded nascent polypeptide chains. This leads to the clearance of misfolded proteins and thus ensures bacterial proteostasis. The results were published in Molecular Cell.
Investigating the chaperone network
Proteins – the building blocks of life – fulfil a large variety of functions in our body. They are synthesized in the cell at large complexes called ribosomes. During this process, information from the messenger RNA is translated into a sequence of amino acids, which are connected to form a polypeptide chain. For proteins to fulfil their function, these nascent polypeptide chains need to be folded into specific three-dimensional structures. How can cells ensure the correct folding of their proteins? This is where chaperones become relevant. The folding helpers ensure that proteins are folded correctly, repair misfolded proteins and initiate the degradation of faulty proteins at the proteasome.
Using quantitative proteomics, Liang Zhao (postdoctoral fellow in the groups of F.-Ulrich Hartl and Manajit Hayer-Hartl) and the team first established an overview of the chaperone network in the model organism Escherichia coli (E. coli). They analyzed E. coli proteins via mass spectrometry and identified a large variety of chaperones important for protein folding at the co-translational level. They found Trigger factor (TF), DnaJ, and DnaK to be the most abundant chaperones. In case of functional loss of the central hub chaperone DnaK, the chaperones HtpG, GroEL and ClpB contribute increasingly to compensate the loss.
Chaperones ensure the correct folding of proteins. Researchers at the MPI of Biochemistry have now discovered a factor that binds to ribosomes and induces the termination of misfolded polypeptide chains, if the chaperon network is defective.
Defects in the chaperone network lead to a response at the ribosome
But what happens at the ribosome when the chaperone network is defective? To investigate this question, the researchers collaborated with Pierre Genevaux and Marie-Pierre Castanié from the University of Toulouse and limited the number of chaperones available in the cell by using knock-out models. They thereby induced misfolding of nascent polypeptide chains. In response, release factor 3 (RF3) was recruited to the ribosome. RF3 subsequently cooperated with another release factor, RF2, leading to the premature termination of protein synthesis and the ensuing release of incomplete misfolded nascent polypeptide chains from the ribosome. That way, the incomplete polypeptide chains could be degraded. Conversely, when this mechanism was inhibited through deletion of RF3, misfolded proteins accumulated in aggregates and impaired the synthesis of new peptide chains. The researchers thus identified, for the first time, a connection between a defect in or limitation of chaperones and an ensuing response involving RF3 at the ribosome. This mechanism is crucial to maintain proteostasis when chaperone availability is restricted as it facilitates clearance of misfolded proteins.
The next steps involve identifying similar mechanism in yeast or mammalian cells. If an analogous mechanism can be found, this might pave the way for future treatments in neurodegenerative diseases such as Alzheimer’s.