| Structural highlights
6hph is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 6hpq, 6hpt, 6hpv |
| Gene: | PIF1, C15orf20 (HUMAN) |
| Activity: | DNA helicase, with EC number 3.6.4.12 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PIF1_HUMAN] DNA-dependent ATPase and 5'-3' DNA helicase required for the maintenance of both mitochondrial and nuclear genome stability. Efficiently unwinds G-quadruplex (G4) DNA structures and forked RNA-DNA hybrids. Resolves G4 structures, preventing replication pausing and double-strand breaks (DSBs) at G4 motifs. Involved in the maintenance of telomeric DNA. Inhibits telomere elongation, de novo telomere formation and telomere addition to DSBs via catalytic inhibition of telomerase. Reduces the processivity of telomerase by displacing active telomerase from DNA ends. Releases telomerase by unwinding the short telomerase RNA/telomeric DNA hybrid that is the intermediate in the telomerase reaction. Possesses an intrinsic strand annealing activity.[HAMAP-Rule:MF_03176][1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Pif1 is a multifunctional helicase and DNA processing enzyme that has roles in genome stability. The enzyme is conserved in eukaryotes and also found in some prokaryotes. The functions of human PIF1 (hPIF1) are also critical for survival of certain tumour cell lines during replication stress, making it an important target for cancer therapy. Crystal structures of hPIF1 presented here explore structural events along the chemical reaction coordinate of ATP hydrolysis at an unprecedented level of detail. The structures for the apo as well as the ground and transition states reveal conformational adjustments in defined protein segments that can trigger larger domain movements required for helicase action. Comparisons with the structures of yeast and bacterial Pif1 reveal a conserved ssDNA binding channel in hPIF1 that we show is critical for single-stranded DNA binding during unwinding, but not the binding of G quadruplex DNA. Mutational analysis suggests that while the ssDNA-binding channel is important for helicase activity, it is not used in DNA annealing. Structural differences, in particular in the DNA strand separation wedge region, highlight significant evolutionary divergence of the human PIF1 protein from bacterial and yeast orthologues.
Structural and functional analysis of the nucleotide and DNA binding activities of the human PIF1 helicase.,Dehghani-Tafti S, Levdikov V, Antson AA, Bax B, Sanders CM Nucleic Acids Res. 2019 Jan 30. pii: 5304331. doi: 10.1093/nar/gkz028. PMID:30698796[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang DH, Zhou B, Huang Y, Xu LX, Zhou JQ. The human Pif1 helicase, a potential Escherichia coli RecD homologue, inhibits telomerase activity. Nucleic Acids Res. 2006 Mar 6;34(5):1393-404. Print 2006. PMID:16522649 doi:http://dx.doi.org/34/5/1393
- ↑ Mateyak MK, Zakian VA. Human PIF helicase is cell cycle regulated and associates with telomerase. Cell Cycle. 2006 Dec;5(23):2796-804. Epub 2006 Dec 1. PMID:17172855
- ↑ Futami K, Shimamoto A, Furuichi Y. Mitochondrial and nuclear localization of human Pif1 helicase. Biol Pharm Bull. 2007 Sep;30(9):1685-92. PMID:17827721
- ↑ Gu Y, Masuda Y, Kamiya K. Biochemical analysis of human PIF1 helicase and functions of its N-terminal domain. Nucleic Acids Res. 2008 Nov;36(19):6295-308. doi: 10.1093/nar/gkn609. Epub 2008, Oct 3. PMID:18835853 doi:http://dx.doi.org/10.1093/nar/gkn609
- ↑ George T, Wen Q, Griffiths R, Ganesh A, Meuth M, Sanders CM. Human Pif1 helicase unwinds synthetic DNA structures resembling stalled DNA replication forks. Nucleic Acids Res. 2009 Oct;37(19):6491-502. doi: 10.1093/nar/gkp671. Epub 2009, Aug 21. PMID:19700773 doi:http://dx.doi.org/10.1093/nar/gkp671
- ↑ Sanders CM. Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity. Biochem J. 2010 Aug 15;430(1):119-28. doi: 10.1042/BJ20100612. PMID:20524933 doi:http://dx.doi.org/10.1042/BJ20100612
- ↑ Paeschke K, Bochman ML, Garcia PD, Cejka P, Friedman KL, Kowalczykowski SC, Zakian VA. Pif1 family helicases suppress genome instability at G-quadruplex motifs. Nature. 2013 May 23;497(7450):458-62. doi: 10.1038/nature12149. Epub 2013 May 8. PMID:23657261 doi:http://dx.doi.org/10.1038/nature12149
- ↑ Dehghani-Tafti S, Levdikov V, Antson AA, Bax B, Sanders CM. Structural and functional analysis of the nucleotide and DNA binding activities of the human PIF1 helicase. Nucleic Acids Res. 2019 Jan 30. pii: 5304331. doi: 10.1093/nar/gkz028. PMID:30698796 doi:http://dx.doi.org/10.1093/nar/gkz028
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