2VXD

The structure of the C-terminal domain of Nucleophosmin

2VXD の概要

• エントリーDOI: 10.2210/pdb2vxd/pdb
• 分子名称: NUCLEOPHOSMIN (1 entity in total)
• 機能のキーワード: chromosomal rearrangement, nuclear protein, proto-oncogene, phosphoprotein, alternative splicing, aml, nucleus, nucleolus, rna-binding, acetylation
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus, nucleolus: P06748
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 6183.12

構造登録者

Bycroft, M.,Grummitt, C.G. (登録日: 2008-07-03, 公開日: 2008-07-15, 最終更新日: 2024-05-15)

主引用文献

Grummitt, C.G.,Townsley, F.M.,Johnson, C.M.,Warren, A.J.,Bycroft, M.
Structural Consequences of Nucleophosmin Mutations in Acute Myeloid Leukemia.
J.Biol.Chem., 283:23326-, 2008

PubMed Abstract: Mutations affecting NPM1 (nucleophosmin) are the most common genetic lesions found in acute myeloid leukemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumor suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukemic 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. 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 we 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 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-leukemia therapeutics.

PubMed: 18511415
DOI: 10.1074/JBC.M801706200

実験手法

SOLUTION NMR