Key points are not available for this paper at this time.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme with multiple cellular functions, including DNA repair, transcriptional regulation, and cell signaling. PARP-1 has a modular architecture with six independent domains comprising the 113-kDa polypeptide. Two zinc finger domains at the N terminus of PARP-1 bind to DNA and thereby activate the catalytic domain situated at the C terminus of the enzyme. The tight coupling of DNA binding and catalytic activities is critical to the cellular regulation of PARP-1 function; however, the mechanism for coordinating these activities remains an unsolved problem. Here, we demonstrate using spectroscopic and crystallographic analysis that human PARP-1 has a third zinc-binding domain. Biochemical mutagenesis and deletion analysis indicate that this region mediates interdomain contacts important for DNA-dependent enzyme activation. The crystal structure of the third zinc-binding domain reveals a zinc ribbon fold and suggests conserved residues that could form interdomain contacts. The new zinc-binding domain self-associates in the crystal lattice to form a homodimer with a head-totail arrangement. The structure of the homodimer provides a scaffold for assembling the activated state of PARP-1 and suggests a mechanism for coupling the DNA binding and catalytic functions of PARP-1. Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme with multiple cellular functions, including DNA repair, transcriptional regulation, and cell signaling. PARP-1 has a modular architecture with six independent domains comprising the 113-kDa polypeptide. Two zinc finger domains at the N terminus of PARP-1 bind to DNA and thereby activate the catalytic domain situated at the C terminus of the enzyme. The tight coupling of DNA binding and catalytic activities is critical to the cellular regulation of PARP-1 function; however, the mechanism for coordinating these activities remains an unsolved problem. Here, we demonstrate using spectroscopic and crystallographic analysis that human PARP-1 has a third zinc-binding domain. Biochemical mutagenesis and deletion analysis indicate that this region mediates interdomain contacts important for DNA-dependent enzyme activation. The crystal structure of the third zinc-binding domain reveals a zinc ribbon fold and suggests conserved residues that could form interdomain contacts. The new zinc-binding domain self-associates in the crystal lattice to form a homodimer with a head-totail arrangement. The structure of the homodimer provides a scaffold for assembling the activated state of PARP-1 and suggests a mechanism for coupling the DNA binding and catalytic functions of PARP-1. Poly(ADP-ribose) polymerase-1 (PARP-1) 3The abbreviations used are: PARPpoly(ADP-ribose) polymerasePARpolymers of ADP-riboseDBDDNA-binding domainBRCTBRCA1 C terminusTCEPTris2-carboxyethyl phosphineSeMetselenomethionineSADsingle-wavelength anomalous dispersion. is a chromatin-associated enzyme involved in multiple cellular processes including DNA repair, cell cycle control, apoptotic signaling, and transcriptional regulation (1D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar, 2Schreiber V. Dantzer F. Ame J.C. de Murcia G. Nat. Rev. Mol. Cell. Biol. 2006; 7: 517-528Crossref PubMed Scopus (1589) Google Scholar, 3Kim M.Y. Zhang T. Kraus W.L. Genes Dev. 2005; 19: 1951-1967Crossref PubMed Scopus (660) Google Scholar). Using NAD+ as a precursor, PARP-1 creates polymers of ADP-ribose (PAR) that can have long and branched structures with up to 200 units (4Alvarez-Gonzalez R. Jacobson M.K. Biochemistry. 1987; 26: 3218-3224Crossref PubMed Scopus (188) Google Scholar, 5Kawaichi M. Ueda K. Hayaishi O. J. Biol. Chem. 1981; 256: 9483-9489Abstract Full Text PDF PubMed Google Scholar). PAR synthesis is initiated on glutamate residues of target proteins, and subsequent polymerization of ADP-ribose units extends from the site of initiation. As a post-translational modification, PAR substantially changes the biophysical and electrostatic properties of a protein and can alter the DNA binding functions, the protein interaction properties, and the cellular location of target proteins (2Schreiber V. Dantzer F. Ame J.C. de Murcia G. Nat. Rev. Mol. Cell. Biol. 2006; 7: 517-528Crossref PubMed Scopus (1589) Google Scholar, 6Kanai M. Hanashiro K. Kim S.H. Hanai S. Boulares A.H. Miwa M. Fukasawa K. Nat. Cell Biol. 2007; 9: 1175-1183Crossref PubMed Scopus (165) Google Scholar). PAR is also a signaling molecule that can initiate a caspase-independent cell death program (7Andrabi S.A. Kim N.S. Yu S.W. Wang H. Koh D.W. Sasaki M. Klaus J.A. Otsuka T. Zhang Z. Koehler R.C. Hurn P.D. Poirier G.G. Dawson V.L. Dawson T.M. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 18308-18313Crossref PubMed Scopus (520) Google Scholar). Humans have as many as 18 PARP enzymes, but PARP-1 is the most abundant and active member of the PARP family (8Ame J.C. Spenlehauer C. de Murcia G. Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1239) Google Scholar). poly(ADP-ribose) polymerase polymers of ADP-ribose DNA-binding domain BRCA1 C terminus Tris2-carboxyethyl phosphine selenomethionine single-wavelength anomalous dispersion. Although PARP-1 modifies several nuclear proteins, the major in vivo target is PARP-1 itself (automodification activity) (1D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar). Automodification modulates the cellular activities of PARP-1 (1D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar, 2Schreiber V. Dantzer F. Ame J.C. de Murcia G. Nat. Rev. Mol. Cell. Biol. 2006; 7: 517-528Crossref PubMed Scopus (1589) Google Scholar, 3Kim M.Y. Zhang T. Kraus W.L. Genes Dev. 2005; 19: 1951-1967Crossref PubMed Scopus (660) Google Scholar). For example, PARP-1 has a structural role in promoting the compaction of chromatin to repress transcription (9Kim M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar). Automodification of PARP-1 releases the enzyme from chromatin, allowing transcriptional machinery to access DNA and thereby controlling gene expression (9Kim M.Y. Mauro S. Gevry N. Lis J.T. Kraus W.L. Cell. 2004; 119: 803-814Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar). PARP-1 also plays a role in DNA damage repair. DNA strand breaks stimulate PARP-1 automodification, and activated PARP-1 recruits DNA repair factors to the site of DNA damage to facilitate repair (10Masson M. Niedergang C. Schreiber V. Muller S. Menissier-de Murcia J. de Murcia G. Mol. Cell. Biol. 1998; 18: 3563-3571Crossref PubMed Scopus (833) Google Scholar, 11El-Khamisy S.F. Masutani M. Suzuki H. Caldecott K.W. Nucleic Acids Res. 2003; 31: 5526-5533Crossref PubMed Scopus (527) Google Scholar). There are several factors that control PARP-1 activity, including self-association, interaction with histones and nucleosomes, NAD+ concentrations, structure-specific binding to DNA, and automodification (1D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar, 2Schreiber V. Dantzer F. Ame J.C. de Murcia G. Nat. Rev. Mol. Cell. Biol. 2006; 7: 517-528Crossref PubMed Scopus (1589) Google Scholar, 3Kim M.Y. Zhang T. Kraus W.L. Genes Dev. 2005; 19: 1951-1967Crossref PubMed Scopus (660) Google Scholar, 12Bauer P.I. Buki K.G. Hakam A. Kun E. Biochem. J. 1990; 270: 17-26Crossref PubMed Scopus (58) Google Scholar). However, there are few molecular level insights into mechanisms that control PARP-1 activity. PARP-1 is 113 kDa (in human) and has a modular architecture composed of multiple, independently folded domains (Fig. 1A). The PARP-1 polypeptide is generally described in three major segments that represent the biochemical activities and functional roles of the enzyme: the DNA-binding domain (DBD; residues 1–374), the automodification domain (residues 375–525), and the catalytic domain (residues 526–1014). The catalytic domain of PARP-1 is located at the C-terminal end of the protein. It is highly conserved in the PARP superfamily, particularly in a region called the PARP signature that is responsible for binding NAD+ (8Ame J.C. Spenlehauer C. de Murcia G. Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1239) Google Scholar, 13Ruf A. Mennissier de Murcia J. de Murcia G. Schulz G.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7481-7485Crossref PubMed Scopus (222) Google Scholar). The automodification domain has a BRCT fold (BRCA1 C terminus). This fold is present in several DNA repair factors and is frequently found to mediate protein-protein interactions (14Bork P. Hofmann K. Bucher P. Neuwald A.F. Altschul S.F. Koonin E.V. FASEB J. 1997; 11: 68-76Crossref PubMed Scopus (660) Google Scholar). Indeed, the BRCT domain of PARP-1 is responsible for the protein-protein interaction that recruits DNA repair enzymes during strand break repair (10Masson M. Niedergang C. Schreiber V. Muller S. Menissier-de Murcia J. de Murcia G. Mol. Cell. Biol. 1998; 18: 3563-3571Crossref PubMed Scopus (833) Google Scholar, 11El-Khamisy S.F. Masutani M. Suzuki H. Caldecott K.W. Nucleic Acids Res. 2003; 31: 5526-5533Crossref PubMed Scopus (527) Google Scholar). The DNA-binding domain is located at the N terminus of PARP-1. The DBD contains two zinc fingers that bind to various DNA structures (15Rolli V. Ruf A. Augustin A. Schulz G.E. Ménissier-de Murcia J. de Murcia G. de Murcia G. Shall S. From DNA Damage and Stress Signalling to Cell Death: Poly ADP-ribosylation a nuclear V. M. H. de Murcia G. Menissier-de Murcia J. J. 11: PubMed Scopus Google and a site S.H. Desnoyers S. Poirier G.G. Res. Google Scholar). and have of the independent domains of PARP-1 (Fig. for the C-terminal region of the the two zinc fingers and the BRCT domain (Fig. a structural analysis of this region to role in PARP-1 and to of the structure of PARP-1 and these domains into an active DNA-dependent enzyme. The two zinc fingers of PARP-1 bind to DNA structures to of the C-terminal catalytic domain of PARP-1 G. de Murcia M. F. M. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1990; PubMed Scopus Google Scholar, M. S. R. T. T. Miwa M. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). The molecular mechanism for coupling the DNA binding and catalytic functions of PARP-1 remains an on structural and biochemical we that the DBD of human PARP-1 contains a third zinc-binding domain. of the new zinc-binding domain is to the DNA binding and catalytic activities of PARP-1. and gene for human PARP-1 (residues and for PARP-1 residues in the expression using that PARP-1 and with an and The of the PARP-1 gene for residues residues and residues in the expression using that the protein and with a C-terminal and using the and and in and in E. 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The at for and at for on a The binding the to a binding DNA-dependent Automodification automodification at in and with DNA as K. E. Kun E. Biochemistry. 2004; PubMed Scopus Google for NAD+ to the and the for various these automodification in a in the of PARP-1 on H. R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). For the with a of The for the of DNA and NAD+ as of the described the the of The on a and the with protein and of and of in at The protein at with an of and in the to and at at the at two for and and the using Z. in anomalous in J. Biol. 1999; PubMed Scopus Google using the at the zinc and at the for The into with from the zinc The used to residues to the of the with of and of the The using the molecular program P. K. Biol. 2004; PubMed Scopus Google J. Biol. 1999; PubMed Scopus Google and in A. in using The using Biol. 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The using that the domain is composed of and and The N terminus of to of a of residues residues and the of this domain of PARP-1 is to this However, that the the structural analysis on the of PARP-1. There are for that can with structure of the multiple of PARP-1 (Fig. we conserved residues and in the domain that of the zinc finger protein fold I. Nucleic Acids Res. 2003; 31: PubMed Scopus Google Scholar). The the residues is conserved the C is and is the of the that bind zinc as of the structure of this domain. analysis that zinc with three and on this there of of zinc in that at molecule of to into the binding properties of the new zinc-binding domain. can frequently for zinc-binding and the spectroscopic properties of a can structural insights into a protein U. M. J.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. A.H. M. Biochem. PubMed Scopus Google Scholar). The of and at from to (Fig. and from to (Fig. The at for is with a a and (Fig. This is present in The at that there are to six of S.W. Biochemistry. PubMed Scopus Google the in the of the (Fig. are of a I. C. Biochem. Google that there are to The at that there of the spectroscopic analysis of that there The at with the of a of to (Fig. the of the and (Fig. This that zinc and that the site as the structure of and with to the as analysis (Fig. that and have the The for PARP-1 analysis of the binding properties of in that residues a zinc The conserved residues and the most zinc of these residues to in to roles as zinc-binding and structural of the protein However, of these to in E. and the of protein analysis of the in this in E. is that the to the of to form a The to also in human PARP-1 to the functional role of the third zinc-binding domain. of these to a in protein in E. as with PARP-1 that the conserved residues are important for of the third zinc-binding region of PARP-1. For the to an of protein for biochemical analysis using the of used for an to that the structure of is to and that the has most a in PARP-1 The in a DNA-dependent automodification and with DNA, and NAD+ to the automodification of the to the and of the PARP-1. these and of PARP-1 H. R. J. Biol. Chem. Full Text PDF PubMed Google in a in PARP-1 on For the form of the protein of with and the of the protein (Fig. of to a in the of highly branched polymers of the for automodification of the (Fig. The of of to that for of to long polymers of ADP-ribose but of is an active enzyme but with for automodification with The zinc fingers of PARP-1 the major DNA binding of the and the zinc fingers bind to DNA with as PARP-1 we that the DNA and binding to DNA using a (Fig. PARP-1 DNA with an of (Fig. with the of K. E. Kun E. Biochemistry. 2004; PubMed Scopus Google Scholar). to DNA with the of (Fig. the third zinc-binding domain of PARP-1 to the DNA binding that PARP-1 activity. This that the automodification of to DNA binding the of to bind DNA with the as the that the has the structure of PARP-1. that the to a of PARP-1 interdomain interactions that the active state of the enzyme. The of the new zinc-binding domain for interdomain using a of the automodification that on protein-protein interactions to activate PARP-1. The DNA-dependent automodification can using two of PARP-1 I. M. M. H. J. Biol. Chem. Full Text PDF PubMed Google 1A). of the PARP-1 polypeptide are to and DNA-dependent automodification I. M. M. H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D. Poirier G.G. J. Cell Sci. PubMed Google Scholar). this of using and of PARP-1 that the and DNA-dependent automodification activity, that there is in of the protein on (Fig. However, in the of DNA-dependent automodification with the of the of the of ADP-ribose polymers (Fig. and are with ADP-ribose in this with the of in a on bind to the DNA used in this the that automodification is protein on the of these two of PARP-1 is protein-protein of PARP-1 that the new zinc-binding DNA-dependent automodification to the with (Fig. This that the third zinc-binding domain of PARP-1 mediates a protein-protein interaction with the C-terminal of and this interdomain is for DNA-dependent automodification of PARP-1. mutagenesis and deletion analysis a role for the new zinc-binding domain in interdomain contacts important for PARP-1 activation. The that the new zinc-binding domain of PARP-1 the DNA binding from the two zinc fingers to the catalytic C terminus to the active form of the enzyme. The the structure of the third zinc-binding domain and thereby the of this of to the structural and functional described we and the structure of the third zinc-binding domain of PARP-1. The crystal structure of using with at the zinc from with The to with a crystallographic and of and (Fig. The crystal structure is with the structural analysis of in zinc is the conserved residues (Fig. the and of the crystal structure are in with the of the analysis of in The fold of of an region (residues a zinc ribbon fold (residues and a C-terminal (residues (Fig. form a at the N with the from the The zinc-binding region a contacts with the The zinc-binding a zinc ribbon fold with I. Nucleic Acids Res. 2003; 31: PubMed Scopus Google Scholar). and form a zinc residues and form a and residues and form a that extends from the of the zinc ribbon on the C-terminal of to the fold of the and the of the C terminus extends from the (Fig. self-associates in the crystal an homodimer that of on (Fig. The C-terminal of the and the third of the and contacts the of the zinc ribbon the of the C-terminal the of the molecule of the The residues that form contacts at the are conserved PARP-1 and (Fig. with the of the the of in crystal structure is to have functional of a of a third zinc-binding domain of PARP-1 that PARP-1 as a zinc-binding protein A. Menissier-de Murcia J. M. F. G. Poirier G. de Murcia G. Nucleic Acids Res. PubMed Scopus Google Scholar, P. K. J. Biochem. PubMed Scopus Google indicate three zinc-binding PARP-1 analysis to bind zinc a PARP-1 found to bind two zinc used the of enzyme and the most the in zinc for a protein. these the of human PARP-1 two zinc fingers in the N terminus of the and subsequent biochemical and structural analysis the of these two zinc fingers G. de Murcia M. F. M. de Murcia G. Proc. Natl. Acad. Sci. U. S. A. 1990; PubMed Scopus Google Scholar, M. S. R. T. T. Miwa M. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). analysis that the of the zinc fingers of PARP-1 indicate a zinc-binding in This the new zinc-binding site has The that a zinc-binding domain and to target the residues for residues to important to the fold of a to the functional role of this domain. Indeed, the to the domain to the that the for crystal structure the of these residues for the structure of the zinc ribbon (Fig. the of the we to insights into the of the new zinc-binding domain biochemical of the (Fig. and the for DNA-dependent automodification (Fig. The automodification, using the and that protein-protein interactions PARP-1 domains are involved in the mechanism of enzyme (Fig. deletion we that the third zinc-binding domain of PARP-1 is for this interdomain The of automodification can in this The the structure for the third zinc-binding domain and thereby the to form interdomain contacts important for enzyme in a for C. E. S. de Murcia G. Menissier-de Murcia J. 1996; PubMed Scopus Google that two in this region of PARP-1 and DNA-dependent DNA crystal structure that of these a that most the fold of the zinc ribbon the region (Fig. are with and the role for the third zinc-binding domain in the DNA binding and catalytic of PARP-1. for these interactions is the of the zinc is and for contacts and contains two conserved residues and that the interdomain interaction described is this of the zinc ribbon fold and the BRCT the BRCT domain mediates protein-protein interactions PARP-1 domains Kim K. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, V. Ame J.C. P. I. V. Menissier-de Murcia J. de Murcia G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). mutagenesis of the third zinc-binding domain to the region that mediates interdomain contacts. This a in PARP-1 domains and with Although the two zinc fingers of PARP-1 are the major to the DNA binding of of PARP-1 also bind to For example, a of PARP-1 (residues from with DNA K.G. Kun E. Biochemistry. PubMed Scopus Google Scholar, J. F. Poirier G. PubMed Scopus Google however, the zinc this DNA binding is structure-specific strand breaks and long segments of DNA The major to the DNA binding properties of the to N terminus Buki K.G. Kun E. Biochemistry. PubMed Scopus Google is of the third zinc-binding domain. For this the region the third zinc-binding domain is frequently described as of the The electrostatic of indicate an DNA-binding but this the of DNA interactions with the third zinc-binding domain. The DNA binding properties of this domain in the of the functional interaction of PARP-1 with structure M.Y. Zhang T. Kraus W.L. Genes Dev. 2005; 19: 1951-1967Crossref PubMed Scopus (660) Google Scholar). of the a for PARP-1 crystal structure of a of and that the PARP-1 polypeptide. The is to these independently folded domains in three the structural of interdomain contacts for that the domain architecture of PARP-1. important of PARP-1 is enzyme PARP-1 is to DNA-dependent enzyme P.I. Buki K.G. Hakam A. Kun E. Biochem. J. 1990; 270: 17-26Crossref PubMed Scopus (58) Google and several of PARP-1 are to form interdomain contacts P.I. Buki K.G. Hakam A. Kun E. Biochem. J. 1990; 270: 17-26Crossref PubMed Scopus (58) Google Scholar, Kim K. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, V. Ame J.C. P. I. V. Menissier-de Murcia J. de Murcia G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K.G. P.I. Hakam A. Kun E. J. Biol. 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However, the molecular of PARP-1 have the mechanisms of PARP-1 and are The homodimer in the crystal lattice of structure provides a for the mechanism of PARP-1 The of at the and the of conserved residues that mediate the interaction that this is an important of the third zinc-binding domain and that is The of the homodimer the N terminus of molecule and the C terminus of the The of the two could as a molecular that the of PARP-1 domains (Fig. this homodimer the BRCT domain is the zinc ribbon domain of a the interaction the third zinc-binding domain and the BRCT domain. this interaction is that the BRCT domain of PARP-1 molecule contacts the zinc-binding domain of the PARP-1 of PARP-1 is during apoptotic the PARP-1 polypeptide the the zinc fingers from the new zinc-binding domain and PARP-1 to a level D. Poirier G.G. J. Cell Sci. PubMed Google Scholar). the DNA binding and catalytic of PARP-1 the the DNA-binding zinc fingers and the third zinc-binding domain that is responsible for DNA binding to the catalytic domain. the of the third zinc-binding domain in to to the third zinc-binding region an mechanism for controlling PARP-1 activity. of residues to the zinc-binding domain and modulates the of human PARP-1 in vivo T.M. S.W. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: PubMed Scopus Google Scholar). residues are located on the the third zinc-binding domain and the BRCT domain. This to a cellular mechanism for controlling PARP-1 regulation of interdomain contacts. PARP-1 plays a role in the cellular to and regulation of PARP-1 is an important mechanism for with of PARP-1 has as a for the cellular to and to and N. D. E. S. M. T. 2005; PubMed Scopus Google Scholar, H. N. M. I. C. A. 2005; PubMed Scopus Google Scholar, M. Poirier G.G. Mol. 2005; 11: Full Text Full Text PDF PubMed Scopus Google Scholar, P. C. Nat. Rev. 2005; PubMed Scopus Google Scholar). for PARP-1 target the of the catalytic domain that is conserved the PARP family of enzymes (8Ame J.C. Spenlehauer C. de Murcia G. Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1239) Google Scholar). the interdomain contacts that are to the of PARP-1 for controlling PARP-1 for structural and biochemical have a third zinc-binding domain in human PARP-1 that is conserved at the level and most at the structural level PARP-1 the two zinc-binding domains of the new zinc-binding domain is for the DNA binding that poly(ADP-ribose) the third zinc-binding domain is involved in protein-protein interactions that PARP-1 and are critical to the DNA-dependent of PARP-1. The crystal structure of the third zinc finger is the of the PARP-1 The is to structural and biochemical to these into a for PARP-1 that can the molecular mechanism for enzyme activation. G. de Murcia for the human PARP-1 and C. P. for critical of the and the at for with with
Langelier et al. (Sat,) studied this question.