Nature Communications paper published (UNC-45/UFD-2)

2018-02-02

It took quite a while to bring this story to the public, possibly because this was our first Ub story. Swimming against the Ub stream, we could show that UNC-45 is not a substrate but rather a co-factor of the UFD-2 ubiquitin ligase targeting muscle myosin for ubiquitination.

Quality control is important – not only in manufacturing, but also for cells that are constantly producing proteins. The cellular quality-control network assists proteins in maintaining their proper fold and full functionality, keeping the amounts of damaged, aggregation-prone molecules at a minimum. To this end, molecular chaperones help proteins reach their native state, while dedicated protease machines eliminate non-functional proteins that cannot be repaired.

In muscle cells, for example, the motor protein myosin needs to fold properly and assemble into filaments to eventually mediate muscle contraction. The UNC-45 protein plays a key role in this process. UNC-45 forms the core of a myosin assembly line allowing various cellular chaperones to work side-by-side when putting myosin filaments together. In our most recent study, published in Nature Communications, we show that the UNC-45 chaperone also participates in the degradation of myosin. Apparently, the dual functions of UNC-45 depend on the partner in crime. During development, UNC-45 collaborates with general chaperones to promote myosin maturation. However, during stress situations, the myosin chaperone can team up with the UFD-2 ubiquitin ligase, a component of the protein degradation system in the cell, marking client proteins for degradation by the proteasome. The specialized UNC-45/UFD-2 death-tagging system, in which an E3 ligase utilizes a specific molecular chaperone as Substrate Positioning System, has exciting implications for how to find and deal with problematic proteins in the cell, as we would like to explore in the time to come.

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