Downloaded from https://academic.oup.com/jmcb/article-abstract/10/4/371/4961362 by Ed 'DeepDyve' Gillespie user on 17 October 2018 doi:10.1093/jmcb/mjy010 Journal of Molecular Cell Biology (2018), 10(4), 371–373 j 371 Published online April 5, 2018 Research Highlight Jumonji domain-containing protein family: the functions beyond lysine demethylation Two of the unsolved but important ques- reported to possess a KDM activity on the and a reactive Fe(IV)=O ferryl intermediate. tions in epigenetics are whether arginine sites K4,K9,K27,and K36 of histone 3 as Addition of substrates in the reaction will dra- demethylases (RDMs) exist and whether pro- well as non-histone substrates in mono-, di-, matically stimulate the process. This iron teolytic cleavage of the histone tails and and tri-methylation forms (Figure 1C). It is (IV)-oxo intermediate then oxidizes the C–H subsequent histone remodeling are a major predictable that the demethylation activity bond and leads to formation of a hydroxy- epigenetic modiﬁcation process. Jumonji of the rest of JmjC-containing proteins and lated product. If the hydroxylation happens domain (JmjC)-containing proteins have their activity on additional substrates will be on methyl group on an amidogen, this pro- been characterized as lysine demethylases identiﬁed upon the availability of technolo- cess will form an unstable hemiaminal. The (KDMs) in a certain degree (Klose et al., gies such as speciﬁc antibodies and sensi- hydroxymethyl is likely spontaneously released 2006). Emerging evidences indicate that tive mass spectrometry. The enzymes are as formaldehyde, resulting in a demethy- they also catalyze demethylation reaction highly expressed during the hematopoietic lated substrate. The process does not dis- on the arginine residues and proteolytic development and may play an important criminate the methylarginine from methylysine. removal of histone tails. These processes role in higher animals and humans. Currently, Hydroxylationisanintermediatestepof are likely associated with biological mean- the vast majority of the identiﬁed biological demethylation. ings. This research highlight is intended to functions of the JmjC-containing proteins are It has been reported recently that two provideabird’seye view of thecurrent attributed to their KDM activity. orphan JmjC-containing proteins, JMJD5 and state of the expanded biochemical proper- While arginine methyl transferases have JMJD7, have divalent cation-dependent pro- ties of JmjC-containing proteins as RDMs and been identiﬁed and their function in cells tease activities that preferentially cleave methylation-dependent histone tail clipping have been well documented (Yang and the tails of histone 3 or 4 containing methy- enzymes. Bedford, 2013; Fuhrmann et al., 2015), RDMs lated lysine or arginine (Figure 1C). After The JmjC-containing proteins are a family have not yet been identiﬁed. Jmjc domain- the initial speciﬁc cleavage, JMJD5 and of non-haeme iron(II) and 2-oxoglutarate containing 6 (JMJD6) was previously reported JMJD7, acting as aminopeptidases, progres- (2OG or α-ketoglutarate)-dependent oxyge- as a putative RDM for asymmetric dimethy- sively digest the C-terminal products, which nases with a characteristic double-stranded larginine (ADMA) and symmetric dimethy- is a methylation-dependent peptidase activ- and antiparallel β-sheet structure. An example larginine (SDMA) histone substrates H3 and ity and also termed as clipping (Liu et al., of JMJD5 (PDB 4gjy) is shown in Figure 1A. H4 (Chang et al., 2007). However, this func- 2017; Shen et al., 2017). Among 23 JmjC Our comprehensive three-dimensional (3D) tion was subjected to conﬂicting reports. domain-containing proteins with crystal 2+ structural alignment of available crystal Two follow-up reports indicated that JMJD6 structures, most of them contain Zn 2+ structures of 23 JmjC-containing proteins only catalyses 2OG-dependent C-5 hydrox- besides Fe , which increases the possibil- indicates that previously identiﬁed aspa- ylation of lysine residues in mRNA splicing- ity for JmjC-containing proteins to act as rate/glutamate and two histone residues regulatory proteins and histones (Webby methyl group-dependent metalloproteases. coordinate the iron(II) cofactor, while two et al., 2009; Mantri et al., 2010). More recently, The orphan subfamily members such as aromatic ring-containing residues (W, Y, or F) a study showed that certain KDMs possess JMJD5 only have two residues to coordinate 2+ play a critical role in stabilizing both iron(II) RDM activity on methylated histone pep- Zn , which could be ﬂexible for peptidase and the catalytic pocket with π-cation inter- tide model substrates (Walport et al., 2016) reaction, similarly to the ones in metallo- actions (Figure 1A). The family has been (Figure 1C). The catalytic mechanism for proteases. In contrast, the members in classiﬁed into seven subfamilies based on JmjC proteins is catalyzing hydroxylation PHF2/PHF8 and JMJD2/JHDM3 subfamilies 2+ their sequences (Klose et al., 2006). Our 3D of C–H bonds and N-demethylation via have four residues to coordinate Zn , structural alignment with TM-score heatmap hydroxylation (Figure 1D). The active site which is rigid, buried, and not accessible to conﬁrms such clustering (Figure 1B). A new Fe(II) is bound by HXD/E…H and cofac- the substrate. For the JARID and UTX/UTY 2+ family member, TYW5,which may ﬁtinto tor 2OG. In the absence of substrates, 2OG- subfamilies, Zn is far away from Fe(II) theorphansubfamily hasbeenidentiﬁed dependent oxygenases often catalyze a slow, catalysis center, which makes it difﬁcult for during our recent search (Figure 1C). So far, uncoupled reaction in which 2OG is decar- a coordinated reaction between methyl group 22 out of 31 family members have been boxylated to form succinate, carbon dioxide, recognition and clipping. Further experiments © The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved. Downloaded from https://academic.oup.com/jmcb/article-abstract/10/4/371/4961362 by Ed 'DeepDyve' Gillespie user on 17 October 2018 372 j Meng et al. Figure 1 Structure similarity, biochemical activities, and catalytic mechanism of JmjC domain-containing protein family. (A) 3D structure depicting the polypeptide backbone of the JmjC domain of JMJD5 (PDB 4gjy) and residues required for iron binding. (B) Structural similarity heatmap for JmjC proteins based on TM-score. The maximum TM-score is used to compare protein structure similarity. (C) Biochemical activities of JmjC proteins. +, oxygenase activity has been detected. (D) Schematics showing the catalytic mechanism of lysine/arginine demethylation mediated by JmjC proteins, including the steps for hydroxylation of the C–H bond and N-methyl group demethylation, via C-hydroxylation, followed by the fragmentation of a hemiaminal intermediate. are warranted to test whether the status of of such a reaction is not clear yet but could rapidly deplete the histones and remodel 2+ Zn in proteins is a determining factor for be involved in transcriptional regulation, DNA the chromatin structure to expose DNA for such a cleavage. The biological signiﬁcance damage response, and apoptosis in order to the necessary reactions. Downloaded from https://academic.oup.com/jmcb/article-abstract/10/4/371/4961362 by Ed 'DeepDyve' Gillespie user on 17 October 2018 JmjC-containing proteins function beyond lysine demethylation j 373 Fe(II)-dependent lysyl hydroxylase JMJD6. J. Mol. [This work was supported by NCI/NIH References Biol. 401, 211–222. Chang, B., Chen, Y., Zhao, Y., et al. (2007). JMJD6 is a R01CA073764.] Shen, J., Xiang, X., Chen, L., et al. (2017). JMJD5 histone arginine demethylase. Science 318, 444–447. cleaves monomethylated histone H3 N-tail under Fuhrmann, J., Clancy, K.W., and Thompson, P.R. 1 2 1 Yuan Meng , Hongzhi Li , Changwei Liu , DNA damaging stress. EMBO Rep. 18, 2131–2143. (2015). Chemical biology of protein arginine 1 1, Li Zheng , and Binghui Shen Walport, L.J., Hopkinson, R.J., Chowdhury, R., et al. modiﬁcations in epigenetic regulation. Chem. (2016). Arginine demethylation is catalysed by a Rev. 115, 5413–5461. Department of Cancer Genetics and subset of JmjC histone lysine demethylases. Nat. Klose, R.J., Kallin, E.M., and Zhang, Y. (2006). Epigenetics, Beckman Research Institute of City Commun. 7, 11974. JmjC-domain-containing proteins and histone of Hope, Duarte, CA 91010, USA Webby, C.J., Wolf, A., Gromak, N., et al. (2009). Jmjd6 demethylation. Nat. Rev. Genet. 7, 715–727. Department of Molecular Medicine, Beckman catalyses lysyl-hydroxylation of U2AF65, a protein Liu, H., Wang, C., Lee, S., et al. (2017). Clipping of Research Institute of City of Hope, Duarte, CA associated with RNA splicing. Science 325, 90–93. arginine-methylated histone tails by JMJD5 and 91010, USA Yang, Y., and Bedford, M.T. (2013). Protein argin- JMJD7.Proc. Natl Acad.Sci.USA 114,E7717–E7726. *Correspondence to: Binghui Shen, ine methyltransferases and cancer. Nat. Rev. Mantri, M., Krojer, T., Bagg, E.A., et al. (2010). E-mail: email@example.com Cancer 13, 37–50. Crystal structure of the 2-oxoglutarate- and
Journal of Molecular Cell Biology – Oxford University Press
Published: Aug 1, 2018
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