Solution structure of the PWWP domain of the hepatoma‐derived growth factor family

Nameki, Nobukazu; Tochio, N.; Koshiba, S.; Inoue, Makoto; Yabuki, Takashi; Aoki, Masaaki; Seki, Eiko; Matsuda, Takayoshi; Fujikura, Yukiko; Saito, Mizuki; Ikari, Masaomi; Watanabe, Megumi; Terada, Takaho; Shirouzu, Mikako; Yoshida, Mayumi; Harada, Hiroshi; Tanaka, Akiko; Hayashizaki, Yoshihide; Güntert, Peter; Kigawa, T.; Yokoyama, Shigeyuki

doi:10.1110/ps.04975305

Cited by 44 publications

(50 citation statements)

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“…The domain is present in diverse chromatin-associated proteins involved in DNA repair, histone modification, transcriptional regulation, and DNA methylation (41)(42)(43). Although the function of the domain is unknown, the PWWP module has been reported to bind DNA without sequence specificity (41,44) and to have methyllysine binding ability (39,40).…”

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confidence: 99%

Role of the PWWP Domain of Lens Epithelium-derived Growth Factor (LEDGF)/p75 Cofactor in Lentiviral Integration Targeting

Gijsbers

Vets

Rijck

et al. 2011

Journal of Biological Chemistry

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LEDGF/p75 is a chromatin-interacting, cellular cofactor of HIV integrase that dictates lentiviral integration site preference. In this study we determined the role of the PWWP domain of LEDGF/p75 in tethering and targeting of the lentiviral pre-integration complex, employing potent knockdown cell lines allowing analysis in the absence of endogenous LEDGF/p75. Deletion of the PWWP domain resulted in a diffuse subnuclear distribution pattern, loss of interaction with condensed chromatin, and failure to rescue proviral integration, integration site distribution, and productive virus replication. Substitution of the PWWP domain of LEDGF/p75 with that of hepatoma-derived growth factor or HDGF-related protein-2 rescued viral replication and lentiviral integration site distribution in LEDGF/p75-depleted cells. Replacing all chromatin binding elements of LEDGF/p75 with full-length hepatoma-derived growth factor resulted in more integration in genes combined with a preference for CpG islands. In addition, we showed that any PWWP domain targets SMYD1-like sequences. Analysis of integration preferences of lentiviral vectors for epigenetic marks indicates that the PWWP domain is critical for interactions specifying the relationship of integration sites to regions enriched in specific histone post-translational modifications.Stable integration of the viral DNA into the host genome is one of the hallmarks of retroviral replication and has profound consequences for both the virus and the host. For the virus it is essential to direct integration in the host cell chromatin to sites that allow efficient gene expression to fulfill a successful infection cycle. Retroviruses from different genera have evolved to integrate their genomic DNA at different sites in the genome of their respective hosts. Human immunodeficiency virus (HIV) and other lentiviruses have a strong preference for integration in active transcription units (1), and murine leukemia virus (MLV) genomes preferentially integrate near transcription start sites and CpG island regions (2), whereas avian sarcoma leukosis virus (3, 4) and the human T-cell leukemia virus display a much weaker preference for these features (5, 6), only weakly favoring integration in active transcription units. Deciphering the mechanisms that dictate integration site selection is instrumental to better understand basic retrovirology and its clinical applications such as drug development and gene therapy.Studies of yeast retrotransposons demonstrated that cellular cofactors determine the integration site preference (7-9). Likewise, interactions between HIV integrase (IN) 4 and the host cell protein lens epithelium-derived growth factor (LEDGF/p75) (10) direct HIV integration targeting. LEDGF/p75 specifically binds IN via its integrase binding domain (LEDGF ) ( Fig. 1) and functions as a molecular tether during lentiviral integration, bridging the viral pre-integration complex (PIC) with the host cell chromatin (11-13). Cells depleted for LEDGF/p75 (13, 14) or somatic knock-out cells (15, 1...

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mentioning

confidence: 99%

Role of the PWWP Domain of Lens Epithelium-derived Growth Factor (LEDGF)/p75 Cofactor in Lentiviral Integration Targeting

Gijsbers

Vets

Rijck

et al. 2011

Journal of Biological Chemistry

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“…The PWWP domain structure of mHRP-3 has recently been determined (Nameki et al 2005). The construct utilized has 75% identity to the PWWP domain of HDGF.…”

Section: Comparison Of the Hdgf Pwwp Domain And Mhrp-3 Structuresmentioning

confidence: 99%

High resolution structure of the HDGF PWWP domain: A potential DNA binding domain

Lukasik¹

2006

Protein Science

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Hepatoma Derived Growth Factor (HDGF) is an endogenous nuclear-targeted mitogen that is linked with human disease. HDGF is a member of the weakly conserved PWWP domain family. This 70-amino acid motif, originally identified from the WHSC1 gene, has been found in more than 60 eukaryotic proteins. In addition to the PWWP domain, many proteins in this class contain known chromatin remodeling domains, suggesting a role for HDGF in chromatin remodeling. We have determined the NMR structure of the HDGF PWWP domain to high resolution using a combination of NOEs, Jcouplings, and dipolar couplings. Comparison of this structure to a previously determined structure of the HDGF PWWP domain shows a significant difference in the C-terminal region. Comparison to structures of other PWWP domains shows a high degree of similarity to the PWWP domain structures from Dnmt3b and mHRP. The results of selected and amplified binding assay and NMR titrations with DNA suggest that the HDGF PWWP domain may function as a nonspecific DNA-binding domain. Based on the NMR titrations, we propose a model of the interaction of the PWWP domain with DNA.

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“…To date, several three-dimensional structures of PWWP domains have been reported, including those of DNMT3a, DNMT3b, Pdp1, Pdp2, HDGF, HDGF2, HDGF-related protein 3 (HRP-3), Bromo and plant homeodomain (PHD) finger-containing protein 1 (BRPF1), BRPF2, BRPF3, LEDGF/ p75, Mutated melanoma-associated antigen 1 (MUM1), MutS homolog 6 (MSH6), and Zinc finger MYND domaincontaining protein 11 (ZMNYD11) (Qiu et al 2002;Slater et al 2003;Sue et al 2004Sue et al , 2007Nameki et al 2005;Lukasik et al 2006;Laguri et al 2008;Vezzoli et al 2010;Wu et al 2011;Eidahl et al 2013;van Nuland et al 2013;Wang et al 2014;Wen et al 2014). Table 1 summarizes the structural data currently available in the literature.…”

Section: Structural Features Of Pwwp Domainsmentioning

confidence: 99%

“…2) (Qiu et al 2002. The β2−β3 loop is the less conserved part of the β−barrel, both in terms of amino acid composition and length, allowing for the insertion of different secondary structural elements (Qiu et al 2002(Qiu et al , 2012Slater et al 2003;Nameki et al 2005;Vezzoli et al 2010;Wu et al 2011).…”

Section: Structural Features Of Pwwp Domainsmentioning

confidence: 99%

“…The stability of the PWWP domain arises from intramolecular hydrogen bonds and polar interactions. These interactions occur not only between residues located in the same substructure but also between residues on different substructures, such as those present in the β1 −β2 arch and β3−β4 loop and the ones in the helical region (Qiu et al 2002(Qiu et al , 2012Slater et al 2003;Nameki et al 2005;Vezzoli et al 2010;Wu et al 2011). …”

Section: Structural Features Of Pwwp Domainsmentioning

confidence: 99%

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PWWP domains and their modes of sensing DNA and histone methylated lysines

2016

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Chromatin plays an important role in gene transcription control, cell cycle progression, recombination, DNA replication and repair. The fundamental unit of chromatin, the nucleosome, is formed by a DNA duplex wrapped around an octamer of histones. Histones are susceptible to various post-translational modifications, covalent alterations that change the chromatin status. Lysine methylation is one of the major post-translational modifications involved in the regulation of chromatin function. The PWWP domain is a member of the Royal superfamily that functions as a chromatin methylation reader by recognizing both DNA and histone methylated lysines. The PWWP domain three-dimensional structure is based on an N-terminal hydrophobic β-barrel responsible for histone methyl-lysine binding, and a C-terminal α-helical domain. In this review, we set out to discuss the most recent literature on PWWP domains, focusing on their structural features and the mechanisms by which they specifically recognize DNA and histone methylated lysines at the level of the nucleosome.

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Solution structure of the PWWP domain of the hepatoma‐derived growth factor family

Cited by 44 publications

References 51 publications

Role of the PWWP Domain of Lens Epithelium-derived Growth Factor (LEDGF)/p75 Cofactor in Lentiviral Integration Targeting

Role of the PWWP Domain of Lens Epithelium-derived Growth Factor (LEDGF)/p75 Cofactor in Lentiviral Integration Targeting

High resolution structure of the HDGF PWWP domain: A potential DNA binding domain

PWWP domains and their modes of sensing DNA and histone methylated lysines

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