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|2vxd, 20 NMR models ()|
The structure of the C-terminal domain of Nucleophosmin
Mutations affecting nucleophosmin (NPM1) are the most common genetic lesions found in acute myeloid leukaemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumour suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukaemic cells. This mutant phenotype is the result of the substitution of several C-terminal residues, including one or two conserved tryptophan residues, with a leucine rich nuclear export signal (NES). The exact molecular mechanism underlying the loss of nucleolar retention, and the role of the tryptophans, remains unknown. In this study we have determined the structure of an independently folded globular domain in the C-terminus of NPM1 using NMR spectroscopy and report that the conserved tryptophans are critical for structure. This domain is necessary for the nucleolar targeting of NPM1 and is disrupted by mutations in AML with cytoplasmic NPM1. Furthermore, we identify conserved surface- exposed lysine residues (K263 and K267) that are functionally rather than structurally important for nucleolar localization. This study provides new focus for efforts to understand the pathogenesis of AML with cytoplasmic NPM1 and may be used to aid the design of small molecules that target the C-terminal domain of NPM1 to act as novel anti-proliferative and anti-leukaemia therapeutics.
Structural consequences of nucleophosmin mutations in acute myeloid leukaemia., Grummitt CG, Townsley FM, Johnson CM, Warren AJ, Bycroft M, J Biol Chem. 2008 May 29;. PMID:18511415
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[NPM_HUMAN] Note=A chromosomal aberration involving NPM1 is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with ALK. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. Note=A chromosomal aberration involving NPM1 is found in a form of acute promyelocytic leukemia. Translocation t(5;17)(q32;q11) with RARA. Note=A chromosomal aberration involving NPM1 is a cause of myelodysplastic syndrome (MDS). Translocation t(3;5)(q25.1;q34) with MLF1. Note=Defects in NPM1 are associated with acute myelogenous leukemia (AML). Mutations in exon 12 affecting the C-terminus of the protein are associated with an aberrant cytoplasmic location.
[NPM_HUMAN] Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF. Binds ribosome presumably to drive ribosome nuclear export. Associated with nucleolar ribonucleoprotein structures and bind single-stranded nucleic acids. Acts as a chaperonin for the core histones H3, H2B and H4. Stimulates APEX1 endonuclease activity on apurinic/apyrimidinic (AP) double-stranded DNA but inhibits APEX1 endonuclease activity on AP single-stranded RNA. May exert a control of APEX1 endonuclease activity within nucleoli devoted to repair AP on rDNA and the removal of oxidized rRNA molecules. In concert with BRCA2, regulates centrosome duplication. Regulates centriole duplication: phosphorylation by PLK2 is able to trigger centriole replication.      
About this Structure
- Grummitt CG, Townsley FM, Johnson CM, Warren AJ, Bycroft M. Structural consequences of nucleophosmin mutations in acute myeloid leukaemia. J Biol Chem. 2008 May 29;. PMID:18511415 doi:M801706200
- ↑ Swaminathan V, Kishore AH, Febitha KK, Kundu TK. Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol Cell Biol. 2005 Sep;25(17):7534-45. PMID:16107701 doi:10.1128/MCB.25.17.7534-7545.2005
- ↑ Ma Z, Kanai M, Kawamura K, Kaibuchi K, Ye K, Fukasawa K. Interaction between ROCK II and nucleophosmin/B23 in the regulation of centrosome duplication. Mol Cell Biol. 2006 Dec;26(23):9016-34. Epub 2006 Oct 2. PMID:17015463 doi:10.1128/MCB.01383-06
- ↑ Maggi LB Jr, Kuchenruether M, Dadey DY, Schwope RM, Grisendi S, Townsend RR, Pandolfi PP, Weber JD. Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome. Mol Cell Biol. 2008 Dec;28(23):7050-65. Epub 2008 Sep 22. PMID:18809582 doi:MCB.01548-07
- ↑ Vascotto C, Fantini D, Romanello M, Cesaratto L, Deganuto M, Leonardi A, Radicella JP, Kelley MR, D'Ambrosio C, Scaloni A, Quadrifoglio F, Tell G. APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA quality control process. Mol Cell Biol. 2009 Apr;29(7):1834-54. doi: 10.1128/MCB.01337-08. Epub 2009 Feb, 2. PMID:19188445 doi:10.1128/MCB.01337-08
- ↑ Krause A, Hoffmann I. Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers centriole duplication. PLoS One. 2010 Mar 24;5(3):e9849. doi: 10.1371/journal.pone.0009849. PMID:20352051 doi:10.1371/journal.pone.0009849
- ↑ Wang HF, Takenaka K, Nakanishi A, Miki Y. BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. Cancer Res. 2011 Jan 1;71(1):68-77. doi: 10.1158/0008-5472.CAN-10-0030. Epub 2010, Nov 16. PMID:21084279 doi:10.1158/0008-5472.CAN-10-0030
- ↑ Chun Y, Park B, Koh W, Lee S, Cheon Y, Kim R, Che L, Lee S. New centromeric component CENP-W is an RNA-associated nuclear matrix protein that interacts with nucleophosmin/B23 protein. J Biol Chem. 2011 Dec 9;286(49):42758-69. doi: 10.1074/jbc.M111.228411. Epub 2011, Oct 14. PMID:22002061 doi:10.1074/jbc.M111.228411