“Transformer” Proteins: Reshaping the role of proteins in cancer progression

According to a recent study published in Angewandte Chemie, researchers at the Scripps Research Institute (TSRI) and St. Jude Children’s Research Hospital have found how proteins involved in cancer transform into different structures that interfere with their normal functions. Scientists are able to detect these transformations using a combination of the following three techniques: single-molecule biophysics, fluorescence resonance energy transfer (FRET) and circular dichroism. More recently, scientists have focused on the nucleophosmin (NPM1) protein. In its normal state, NPM1 does not have a defined structure but rather morphs between a monomer and a five-subunit folded pentamer. Mutations of this protein interfere with its ability to suppress tumors, one of its many normal functions. Mutated NPM1 has been found in cancers such as non-Hodgkin lymphoma and acute myelogenous leukemia.

As NPM1 morphs between its two forms, it takes different pathways. For example, one such transformation occurs when phosphoryl groups attach to NPM1. The phosphorylation causes the ordered pentamer form to become disordered and leave the cell’s nucleus, whereby a binding partner initiates reverse transformation to a pentamer. However, NPM1 does not take the same path back to re-enter the nucleolus. There are many intermediate steps between the transition from monomer to pentamer that are at the whim of changing conditions such as salt levels, phosphorylation, and binding partners. Future studies using the three techniques listed above to detect transformations, along with a technique to label proteins for single-molecule fluorescence, may also allow insight into other conditions related to protein disorder and folding, such as neurodegenerative disease, heart disease, infectious disease, and type 2 diabetes.

What are some of the other benefits of researching the effects of protein restructuring? What are the possible therapeutic advantages of understanding how transforming proteins affect disease?

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