1hn3
From Proteopedia
SOLUTION STRUCTURE OF THE N-TERMINAL 37 AMINO ACIDS OF THE MOUSE ARF TUMOR SUPPRESSOR PROTEIN
Structural highlights
FunctionARF_MOUSE Capable of inducing cell cycle arrest in G1 and G2 phases (PubMed:8521522, PubMed:9393858). Acts as a tumor suppressor (PubMed:8521522, PubMed:9393858, PubMed:15601844, PubMed:17936562). Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus (PubMed:9529248, PubMed:10359817). This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis (PubMed:10359817). Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes (PubMed:15361884). Binds to BCL6 and down-regulates BCL6-induced transcriptional repression (PubMed:15567177). Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression (By similarity). Binds to TOP1/TOPOI and stimulates its activity (By similarity). This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation (By similarity). Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing (By similarity). Plays a role in inhibiting ribosome biogenesis, perhaps by binding to the nucleolar localization sequence of transcription termination factor TTF1, and thereby preventing nucleolar localization of TTF1 (PubMed:20513429). Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination (By similarity). Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1 (By similarity). Binds to HUWE1 and represses its ubiquitin ligase activity (By similarity). May play a role in controlling cell proliferation and apoptosis during mammary gland development (By similarity).[UniProtKB:Q8N726][1] [2] [3] [4] [5] [6] [7] [8] [9] May be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.[10] Publication Abstract from PubMedArf is a tumor suppressor that regulates p53 function and is a frequent target for loss in human cancers. Through two novel mechanisms, Arf inhibits the oncoprotein Hdm2, a negative regulator of p53. (1) Arf inhibits the E3 ubiquitin ligase activity of Hdm2 that leads to p53 degradation, and (2) Arf sequesters Hdm2 within nucleoli. These activities of Arf promote p53-mediated cell cycle arrest and apoptosis. Fundamental to these processes are interactions between Arf and Hdm2. Here we show that a peptide containing the 37 N-terminal amino acids of mouse Arf (mArfN37) localizes to nucleoli, sequesters Hdm2 within nucleoli, and causes cell cycle arrest. Circular dichroism and NMR spectroscopy show that mArfN37 is largely unstructured under aqueous conditions; however, the peptide adopts two alpha-helices (helix 1, residues 4-14; and helix 2, residues 20-29) in 2,2,2-trifluoroethanol (TFE). Each helix contains an amino acid motif that is repeated twice in mArfN37, once in each helix. The two helices, however, do not interact but are connected by an apparently flexible linker. The repeated motif contains Arg residues spaced by a hydrophobic segment that may be involved in Hdm2 recognition and binding. The RRPR nucleolar localization signal, contained within residues 31-34, appears to be disordered under all conditions. The identification of two Arf structural modules suggests that short peptides containing the repeated motif may function as Arf mimics and may allow the design of small molecule Arf mimics in the future. Solution structure of the p53 regulatory domain of the p19Arf tumor suppressor protein.,DiGiammarino EL, Filippov I, Weber JD, Bothner B, Kriwacki RW Biochemistry. 2001 Feb 27;40(8):2379-86. PMID:11327858[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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