Rock'n'roll mechanism helps to target proteins for degradation

MPIB researchers discovered a mechanism that recycles protein modules to enable targeted degradation of unwanted proteins and thus avoid problems in the cellular supply chain.

May 02, 2023

Martinsried. Researchers led by Brenda Schulman, director at the Max Planck Institute of Biochemistry (MPIB), discovered a new mechanism using cryo-EM, that is essential for the targeted degradation of unwanted proteins in cells. The "rock-and-roll mechanism" describes how cullin-RING ligase (CRL) reuses protein modules that are crucial for protein degradation to activate new molecular machines all the time. The findings of the study, which they conducted in collaboration with scientists at St. Jude Children’s Research Hospital, offer great potential for possible new therapies for diseases such as cancer. The results were published in the journal Cell.

Cells depend on "molecular machines", that just like real machines, perform the work inside cells. Molecular machines need to be ready when cells need them to carry out urgent tasks and need to be turned off once their work is done. These cellular machines are often assembled from parts, called protein modules, that contain groups of different proteins.

One important type of molecular machine, called a cullin-RING ligase, or CRL for short, prevents buildup of cellular ‘garbage’ – damaged or superfluous proteins. A CRL attaches a tag, called ubiquitin, to such unwanted proteins. Human cells have hundreds of different CRLs that tag different types of proteins needing elimination. Each CRL has two modules: one that is common to all CRLs and performs the tagging with ubiquitin, and another one that is a specificity factor, that recognizes a particular type of cellular garbageCells also have hundreds of different specificity factors that each need to connect with a cullin-RING module. When all goes well, the specify factors only go after unnecessary, damaged, or toxic proteins while leaving other proteins untouched. Mutations in a CRL module can therefore cause unwanted buildup of damaged or misfunctioning proteins, leading to diseases including cancers, hypertension, and developmental disorders.

Several years ago, it became apparent that there are too few copies of the common CRL part, the cullin-RING module, in cells to connect with all of the specificity factors and form all possible CRLs at the same time. This raised the important question of how, if an unwanted protein appears, the correct CRL would be available to tag it for elimination. Researchers in the laboratories of Brenda Schulman and Matthias Mann at the Max Planck Institute of Biochemistry, and at St. Jude Children's Research Hospital, set out to solve this central question.

A protein called CAND1 was a potential candidate that could solve the supply chain problem. CAND1 takes the cullin-RING module out of CRLs whose targets do not need tagging and matches it with the correct specificity module to attach ubiquitin to unwanted proteins. Such recycling of a part of one molecular machine and redistribution to others had never been visualized before.

Seeing a machine doing its job is the best way to understand how it works. The researchers therefore used an imaging method called cryo-electron microscopy (cryo-EM), that allows seeing individual molecular machines in action. Dr. Kheewoong Baek, postdoctoral researcher and co-first author of the study, obtained cryo-EM images that when combined produce a spectacular “movie” of how CAND1 takes the cullin-RING module from one CRL and connects it with another specificity factor to create a new molecular machine. The authors describe this process as a ‘rock-and-roll mechanism’, reflecting how the different protein modules move around each other to disassemble and form CRLs. Co-authors Daniel Scott and Lukas Henneberg showed that the rock-and-roll mechanism allows CRLs to form as needed to prevent unwanted proteins from running rampant within the cell.

These results still left the fundamental question unanswered. So why do cells have a supply chain problem in the first place, instead of simply making all possible CRL molecular machines? The rock-and-roll mechanism ensures that only CRLs whose garbage needs tagging are assembled at any given time. The critical insight came from considering that CAND1 and NEDD8, another protein they had already studied before, might together regulate the timing of CRL disassembly. NEDD8 protects those CRLs that are busy doing essential cellular work, so that only the unprotected ones have their cullin-RING module extracted by CAND1. This elegant mechanism ensures that cells always have the right set of CRLs available and helps them to avoid supply chain problems. It also prevents the buildup of unwanted CRL molecular machines. By considering real life machines, it is easy to understand that if unnecessary machines were likewise disassembled and parts constantly reused, this would contribute to environmental sustainability.

Beyond their biological roles, CRLs are of great interest for many biotech and pharmaceutical companies as they can be made to degrade disease-causing proteins. Since CAND1 can use the rock-and-roll mechanism to assemble molecular machines that perform ‘targeted protein degradation’, the new insights offer great hope that CRLs could be commonly used for novel therapeutic technologies to combat cancers and other diseases.

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