6m3i

From Proteopedia

Crystal structure of HPF1/PARP1 complex

Structural highlights

6m3i is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.98Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HPF1_HUMAN Acts as a cofactor for serine ADP-ribosylation by conferring serine specificity on PARP1 and PARP2: interacts with PARP1 and PARP2 and is able to change amino acid specificity toward serine (PubMed:28190768, PubMed:29480802). Promotes histone serine ADP-ribosylation in response to DNA damage, limiting DNA damage-induced PARP1 hyper-automodification, and ensuring genome stability (PubMed:27067600, PubMed:28190768). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). HPF1 also promotes tyrosine ADP-ribosylation, probably by conferring tyrosine specificity on PARP1 (PubMed:30257210).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human HPF1/PARP1-CAT DeltaHD complex at 1.98 A resolution, and mouse and human HPF1 at 1.71 A and 1.57 A resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1.

HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones.,Sun FH, Zhao P, Zhang N, Kong LL, Wong CCL, Yun CH Nat Commun. 2021 Feb 15;12(1):1028. doi: 10.1038/s41467-021-21302-4. PMID:33589610^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gibbs-Seymour I, Fontana P, Rack JGM, Ahel I. HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity. Mol Cell. 2016 May 5;62(3):432-442. doi: 10.1016/j.molcel.2016.03.008. Epub 2016 , Apr 7. PMID:27067600 doi:http://dx.doi.org/10.1016/j.molcel.2016.03.008
↑ Bonfiglio JJ, Fontana P, Zhang Q, Colby T, Gibbs-Seymour I, Atanassov I, Bartlett E, Zaja R, Ahel I, Matic I. Serine ADP-Ribosylation Depends on HPF1. Mol Cell. 2017 Mar 2;65(5):932-940.e6. doi: 10.1016/j.molcel.2017.01.003. Epub, 2017 Feb 9. PMID:28190768 doi:http://dx.doi.org/10.1016/j.molcel.2017.01.003
↑ Palazzo L, Leidecker O, Prokhorova E, Dauben H, Matic I, Ahel I. Serine is the major residue for ADP-ribosylation upon DNA damage. Elife. 2018 Feb 26;7. pii: 34334. doi: 10.7554/eLife.34334. PMID:29480802 doi:http://dx.doi.org/10.7554/eLife.34334
↑ Bartlett E, Bonfiglio JJ, Prokhorova E, Colby T, Zobel F, Ahel I, Matic I. Interplay of Histone Marks with Serine ADP-Ribosylation. Cell Rep. 2018 Sep 25;24(13):3488-3502.e5. doi: 10.1016/j.celrep.2018.08.092. PMID:30257210 doi:http://dx.doi.org/10.1016/j.celrep.2018.08.092
↑ Sun FH, Zhao P, Zhang N, Kong LL, Wong CCL, Yun CH. HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones. Nat Commun. 2021 Feb 15;12(1):1028. PMID:33589610 doi:10.1038/s41467-021-21302-4