The nucleolus is a crucial membrane-less structure or organelle that takes up about 25% of the nucleus of a mammalian cell. The largest membrane-less organelle, the nucleolus has been compared to a manufacturing hub, since one of its main functions is to assemble the ribosomes that produce all of the proteins required by cells. The nucleolus is home to a vast array of proteins, RNA, and other molecules, however, its molecular foundation is unknown.
Now, a study from researchers at St. Jude Children’s Research Hospital has determined that the protein nucleophosmin (NPM1) serves as the glue that holds proteins and RNA together in the nucleolus, showing how NPM1’s structure makes it ideal for the job. The team states their findings come amid intense scientific interest in the role liquid-liquid phase separation plays in promoting membrane-less organelle assembly as well as in performing the molecular processes that occur within them. The opensource study is published in the journal eLife.
Previous studies show NPM1 is an important regulatory protein that is abundant in the nucleolus. NPM1 is known in part for its role in tumor suppression as a binding partner of the tumor suppressor protein ARF. NPM1 includes segments that fold into a rigid, five-sided pentamer and other segments rich in flexible, negatively charged amino acids that bind transiently to other proteins. Earlier studies from the lab demonstrated how under certain conditions the NPM1 pentamer unfolds into a single disordered strand of amino acids. Data also showed that this disordered strand prevented binding to proteins like ARF that include short amino acid sequences rich in the amino acid arginine. The current study identifies the interactions that stem from these segments and allow NPM1 to form loose networks with multiple proteins and RNAs within the cell nucleus.
The current study utilized a variety of imaging, structural, and biophysical laboratory techniques to identify NPM1 as a crucial element for the assembly process within the nucleolus. Results show that the structure of NPM1 allows it to bind to a wide variety of proteins as well as to RNA in different, specific ways that promote phase separation and retain NPM1 and other proteins in the nucleolus. Data findings show that NPM1 forms networks of interactions with other molecules in the nucleolus, loosely gluing nucleolar components together.
Results show incorporation within the nucleolus required NPM1 binding with both nucleolar proteins that include the arginine-rich segments and ribosomal RNA. The group also identified where on the pentamer protein and RNA binding occurred and how the different bonds promoted condensation into liquid-like droplets.
The team surmises that there are other proteins in the nucleolus that have some of the same features as NPM1, including the negatively charged amino acid tracts. For the future, the researchers state that this suggests NPM1 is probably not the only protein contributing to phase separation in the nucleolus and needs further investigation.
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