Chaperone molecules are an important part of protein dynamics for daily cellular function. Misfolded proteins are nonfunctional and can cause cell damage. To prevent this, cells have evolved an arsenal of chaperones that assist with folding and carry out protein quality control. Just like an acrobatic duo, some proteins lend each other stability, which is exactly what researchers at the Biozentrum of the University of Basel have discovered happens for a specific Escherichia coli chaperone called Trigger Factor (TF). The Basel team found that TF recognizes a partner by unstable, flexible domains, to then together form a stable protein duo.   

Findings from the new study were published recently in Nature Communications in an article entitled “The Dynamic Dimer Structure of the Chaperone Trigger Factor.”

In E. coli, TF protects the newly produced proteins from misfolding. The investigators have shown for the first time that TFs also recognize and stabilize each other. Just like single acrobats from a duo, single TF chaperones stand on shaky legs—only as a pair do they find a stable position.

“In unpaired TF proteins, the region that would bind to the ribosome is folded unfavorably and therefore energetically unstable,” explained senior study investigator Sebastian Hiller, Ph.D., a group leader at the Biozentrum. “In the search for an energetically favorable, stable structure, this labile domain is continuously reoriented. TFs are able to detect such dynamic regions of a protein, also among each other.” In combining, the two unstable TF proteins, like two acrobats connecting at the crucial point, form a stable spatial arrangement.

Within one single bacterial cell, more than 10,000 ribosomes produce proteins nonstop. These factories link the individual protein components to form a long peptide chain and transport it outward through a narrow channel. The chaperone TF, which is bound to the tunnel exit of the ribosome, receives the freshly assembled protein and, while shielding it from the environment, helps it to fold correctly. When the protein has found its correct spatial structure, it is released from the chaperone and can get on with its work in the cell.

In the cell, there are considerably more TF proteins than ribosomes. This ensures that the X-thousand ribosomes are fully occupied and that each of the newly produced proteins can be collected. The surplus TF proteins, like acrobatic pairs, join with a partner to form a stable duo. The pairing happens completely on its own.

In the current study, the research team wrote that they determined TF “structure by a combination of high-resolution NMR [nuclear magnetic resonance] spectroscopy and biophysical methods. TF forms a symmetric head-to-tail dimer, where the ribosome binding domain is in contact with the substrate binding domain, while the peptidyl-prolyl isomerase domain contributes only slightly to the dimer affinity. The dimer structure is highly dynamic, with the two ribosome binding domains populating a conformational ensemble in the center. These dynamics result from intermolecular in trans interactions of the TF client-binding site with the ribosome binding domain, which is conformationally frustrated in the absence of the ribosome.”

“The latest findings about the dynamics of stable TF-duos make it possible to draw important conclusions about the functioning of chaperones,” Dr. Hiller added. “Upon recognition, they do not form just one type of protein structure but rather a dynamic ensemble of different spatial arrangements. It is becoming apparent that this functionality is a general pattern for chaperones.”

The elucidation and understanding of the chaperone function at the atomic level are important to the research community worldwide. Problems in the folding process of proteins are associated with various diseases, such as cystic fibrosis, cancer, or Alzheimer's disease.








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