Structural characterization of the C-terminal domain of human nucleophosmin, NPM1

<P>NPM1 IS A MULTIFUNCTIONAL PHOSPHOPROTEIN WHICH SHUTTLES BETWEEN NUCLEUS AND CYTOPLASM. WHEN NPM1 INTERACTS WITH P53, A MUTATION IN ITS C-TERMINUS LEADS TO SEQUESTRATION OF P53 INTO CYTOPLASM, PREVENTING IT FROM GOING INTO THE NUCLEUS. WE HAVE CARRIED OUT STRUCTURAL STUDIES ON THE 53 RESIDUE C-TERMINAL DOMAIN OF HUMAN NPM1, WHICH COMPRISES AN AROMATIC RICH REGION, CONTAINING TWO TRYPTOPHAN RESIDUES. USING NMR, WE FOUND THAT THE C-TERMINAL DOMAIN OF NPM1 IS MADE UP OF 3 ALPHA-HELICES, EACH ENCOMPASSING 10-12 AMINO ACIDS. IT FORMS A TERTIARY STRUCTURE RESEMBLING A TRIANGLE WITH N AND C-TERMINI OF THE DOMAIN COMING TOGETHER. THIS STRUCTURE WILL SERVE AS A PEDESTAL TOWARDS MAPPING THE REGIONS IN NPM1 INVOLVED IN BINDING TO P53. THE INFORMATION OBTAINED WILL PROVIDE AN INSIGHT INTO DEVELOPMENT OF SMALL-MOLECULE DRUGS WHICH COULD PREVENT THE BINDING OF NPM TO P53 AND ALLOWING IT TO CARRY OUT ITS TRANSCRIPTIONAL FUNCTION LEADING TO APOPTOSIS. </P>

Author dc:creator

• AMBALIKA SAGARIKA KHADRIA

• NPM1, AML, p53, NMR, apoptosis, CNS