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A finishing school for proteins

Deciphering the conformational cycle of the molecular chaperone BiP

Munich, 01/12/2011

Proteins form the labour force of the cell. Each protein can perform its particular function only if it folds into a specific shape. Misfolded proteins have a strong tendency to clump, forming insoluble aggregates that are associated with serious disabilities such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Molecular chaperones (so called because they favorably influence the behaviour of their substrates) intervene, often during protein synthesis, to prevent such misfolding. A team led by Professors Don C. Lamb of the Department of Chemistry at LMU Munich and Johannes Buchner of the Technische Universität (TU) München have now taken a closer look at how a major chaperone called BiP performs this role. The researchers specifically asked how BiP’s conformation changes from the moment it binds to a substrate up until the substrate is released and how the co-chaperone ERdJ3 influences its functional cycle. To follow conformational changes, the team made use of a technique known as FRET (Förster Resonance Energy Transfer), which allows one to measure distances (on the order of nanometers) within and between interacting proteins. The results show that two large domains in BiP interact with each other, and that ErdJ3 modulates this interaction in a striking way. (Nature Structural & Molecular Biology online, 9. January 2011)

Folding, assembly and quality control of about one-third of all proteins take place in the so-called endoplasmic reticulum (ER), a system of linked membranous tubes within the cell. Molecular chaperones, including the protein BiP, play a decisive role in all of these processes, helping their substrates to find their correct shapes. Interestingly, chaperones also seem to facilitate protein degradation. Based on measurements taken using the FRET method, the authors of the new study show that BiP consists of two distinct domains, each of which influences the structure, and so also the function, of the other.

One of the domains binds substrates and has a kind of lid. The study revealed that when BiP was bound to an authentic substrate protein, this lid was held in an open position. On the other hand, when a short protein fragment (in this case, a peptide consisting of only seven amino acids) bound to the chaperone, the lid closed. “This finding is interesting because the pharmaceutical industry often uses only short peptides, rather than whole proteins, for binding tests, because they are much easier to handle,“ says Professor Don C. Lamb of the Department of Chemistry at LMU Munich. “We have now clearly shown that BiP can discriminate between a short peptide and a long unfolded protein molecule, even though it recognizes and interacts with the same amino acid sequence in both cases.“

Exactly how the molecular lid behaves is dependent on BiP’s accessory protein ERdJ3. This co-chaperone itself binds to BiP and facilitates its interaction with substrates by keeping the lid in a protein-accepting state. “Our results demonstrate that ERdJ3 essentially puts the chaperone in a position to bind its natural substrates,” says Professor Buchner from the Department of Chemistry at TU Munich. “In fact, the co-chaperone interacts directly with several regions of BiP. Overall, our findings indicate that the function of BiP involves complex and intricate interactions between the chaperone co-chaperone and substrate.“ (suwe)

The study was carried out under the auspices of the Cluster of Excellence ”Nanosystems Initiative Munich“ (NIM) and the Center for Integrated Protein Science Munich (CiPSM), the International Doctorate Program NanoBioTechnology (IDK-NBT) funded by the Bavarian Elite Network, the International Graduate School of Science and Engineering (IGSSE) at TU Munich, the SFB 749, the Chemistry Industry Endowment Fund and the LMUInnovativ BioImaging Network.

 

Publication:
Substrate discrimination of the chaperone BiP by autonomous and cochaperone-regulated conformational transitions
Moritz Marcinowski, Matthias Höller, Matthias J. Feige, Danae Baerend, Don C. Lamb, Johannes Buchner
Nature Structural & Molecular Biology online, 9. January 2011

Contact:
Prof. Dr. Don C. Lamb
Department of Chemistry, LMU Munich
Phone: +49 (0) 89 / 2180 – 77564
Fax: +49 (0)  89 / 2180 – 77560
Email: d.lamb@lmu.de
Web: www.cup.uni-muenchen.de/pc/lamb/index.html

Prof. Dr. Johannes Buchner
Department of Chemistry, TU Munich
Phone: +49 (0) 89 / 2190  13340
Email: Johannes.Buchner@ch.tum.de

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