Multitasking protein: Nucleophosmin 1

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  • Published: Jul 15, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Multitasking protein: Nucleophosmin 1

Many parts to play

Nuclear magnetic resonance spectroscopy has been used to demonstrate how one segment of an important regulatory protein, nucleophosmin 1 (NPM1), helps it to fulfil several roles, including tumour suppression, according to researchers at St Jude Children's Research Hospital and the Medical Research Council Laboratory of Molecular Biology, in Cambridge, UK. The findings could have implications for the development of novel anticancer drugs. Credit: Wikimedia user Emw http://commons.wikimedia.org/wiki/User:Emw

Nuclear magnetic resonance spectroscopy has been used to demonstrate how one segment of an important regulatory protein, nucleophosmin 1 (NPM1), helps it to fulfil several roles, including tumour suppression, according to researchers at St Jude Children's Research Hospital in Memphis, Tennessee and the Medical Research Council Laboratory of Molecular Biology, in Cambridge, UK. The findings could have implications for the development of novel anticancer drugs.

NPM1 plays a critical part not only in tumour suppression but in cell division, protein production and various other cell processes. Until now, however, scientists did not have a clear understanding of how NPM1 carried out its various roles. Now, the researchers report a possible answer in the Proceedings of the National Academy of Sciences (PNAS).

Protein function follows form, which is derived from the order of amino acids in the protein chain. It was previously assumed that the NPM1 segment was always folded into a highly ordered five-sided structure called a pentamer. However, NMR spectroscopy and other techniques have now revealed a regulatory mechanism that stimulates the NPM1 segment to partially or completely unfold into a single disordered strand of amino acids. It is this unfolding that changes the protein's role in different contexts.

Anticancer foundation

"We propose that this regulated unfolding - from a folded pentamer to a disordered monomer - controls how NPM1 functions in cells, including how it interacts with one of the most important tumour suppression proteins, the ARF [alternate reading frame] protein," explains team member Richard Kriwacki of St. Jude's Department of Structural Biology. ARF is lost in a number of cancers, including leukaemia, melanoma and the brain cancer glioblastoma.

Kriwacki adds that this is the first evidence reported that shows how ARF and NPM1 interact at the molecular level. "Our findings provide a foundation for anticancer drug development based on this interaction and will advance understanding of a number of other important cell functions," he adds.

To function properly, ARF must partner with NPM1, so Kappler and colleagues have now detailed the chemical basis of this partnership to demonstrate how changing the shape of the NPM1 segment disrupts the connection. It turns out that the short arginine-rich amino acid sequences present in ARF are key to promoting the binding relationship with the NPM1 pentamer. ARF is, in fact, merely one of several hundred proteins that can bind to NPM1. Moreover, four of every ten of these proteins carries the same arginine-rich sequence, which one must now assume is the commonality between them that gives rise to the binding to NPM1.

Phosphorylation sites

The current research has also now exposed the regulatory mechanism responsible for the shape shifting that NPM1 undergoes: phosphorylation, it turns out, destabilizes the pentamer at the protein's end and thus also disrupts ARF binding; phosphorylation is widely used in cells to regulate how proteins function. Destabilization of the NPM1 segment leads to partial unfolding of the protein, which exposes additional putative phosphorylation sites on NPM1, which then induces further unfolding.

Team member Diana Mitrea suggests that the shape change dictates not only NPM1's binding partners but perhaps also where and how the protein functions in cells. NPM1 is usually found in the nucleolus of the cell within the nucleus. Kriwacki and his colleagues are pursuing the possibility that NPM1 might contribute to the formation of intriguing networked structures with drop-like features present in the nucleolus and discovered as recently as 2009.

Related Links

Proc Natl Acad Sci, 2014, 111, 4466-4471: "Structural polymorphism in the N-terminal oligomerization domain of NPM"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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