2vxd
The structure of the C-terminal domain of Nucleophosmin
Structural highlights
Disease[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. Function[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.[1] [2] [3] [4] [5] [6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedMutations 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[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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