| 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]
Publication Abstract from PubMed
How the self-assembly of partially disordered proteins generates functional compartments in the cytoplasm and particularly in the nucleus is poorly understood. Nucleophosmin 1 (NPM1) is an abundant nucleolar protein that forms large oligomers and undergoes liquid-liquid phase separation by binding RNA or ribosomal proteins. It provides the scaffold for ribosome assembly but also prevents protein aggregation as part of the cellular stress response. Here, we use aggregation assays and native mass spectrometry (MS) to examine the relationship between the self-assembly and chaperone activity of NPM1. We find that oligomerization of full-length NPM1 modulates its ability to retard amyloid formation in vitro. Machine learning-based structure prediction and cryo-electron microscopy reveal fuzzy interactions between the acidic disordered region and the C-terminal nucleotide-binding domain, which cross-link NPM1 pentamers into partially disordered oligomers. The addition of basic peptides results in a tighter association within the oligomers, reducing their capacity to prevent amyloid formation. Together, our findings show that NPM1 uses a "grappling hook" mechanism to form a network-like structure that traps aggregation-prone proteins. Nucleolar proteins and RNAs simultaneously modulate the association strength and chaperone activity, suggesting a mechanism by which nucleolar composition regulates the chaperone activity of NPM1.
A "grappling hook" interaction connects self-assembly and chaperone activity of Nucleophosmin 1.,Saluri M, Leppert A, Gese GV, Sahin C, Lama D, Kaldmae M, Chen G, Elofsson A, Allison TM, Arsenian-Henriksson M, Johansson J, Lane DP, Hallberg BM, Landreh M PNAS Nexus. 2023 Jan 6;2(2):pgac303. doi: 10.1093/pnasnexus/pgac303. eCollection , 2023 Feb. PMID:36743470[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ Saluri M, Leppert A, Gese GV, Sahin C, Lama D, Kaldmäe M, Chen G, Elofsson A, Allison TM, Arsenian-Henriksson M, Johansson J, Lane DP, Hällberg BM, Landreh M. A "grappling hook" interaction connects self-assembly and chaperone activity of Nucleophosmin 1. PNAS Nexus. 2023 Jan 6;2(2):pgac303. PMID:36743470 doi:10.1093/pnasnexus/pgac303
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