Jumonji domain-containing protein family: the functions beyond lysine demethylation

Jumonji domain-containing protein family: the functions beyond lysine demethylation Two of the unsolved but important questions in epigenetics are whether arginine demethylases (RDMs) exist and whether proteolytic cleavage of the histone tails and subsequent histone remodeling are a major epigenetic modification process. Jumonji domain (JmjC)-containing proteins have been characterized as lysine demethylases (KDMs) in a certain degree (Klose et al., 2006). Emerging evidences indicate that they also catalyze demethylation reaction on the arginine residues and proteolytic removal of histone tails. These processes are likely associated with biological meanings. This research highlight is intended to provide a bird’s eye view of the current state of the expanded biochemical properties of JmjC-containing proteins as RDMs and methylation-dependent histone tail clipping enzymes. The JmjC-containing proteins are a family of non-haeme iron(II) and 2-oxoglutarate (2OG or α-ketoglutarate)-dependent oxygenases with a characteristic double-stranded and antiparallel β-sheet structure. An example of JMJD5 (PDB 4gjy) is shown in Figure 1A. Our comprehensive three-dimensional (3D) structural alignment of available crystal structures of 23 JmjC-containing proteins indicates that previously identified asparate/glutamate and two histone residues coordinate the iron(II) cofactor, while two aromatic ring-containing residues (W, Y, or F) play a critical role in stabilizing both iron(II) and the catalytic pocket with π-cation interactions (Figure 1A). The family has been classified into seven subfamilies based on their sequences (Klose et al., 2006). Our 3D structural alignment with TM-score heatmap confirms such clustering (Figure 1B). A new family member, TYW5, which may fit into the orphan subfamily has been identified during our recent search (Figure 1C). So far, 22 out of 31 family members have been reported to possess a KDM activity on the sites K4, K9, K27, and K36 of histone 3 as well as non-histone substrates in mono-, di-, and tri-methylation forms (Figure 1C). It is predictable that the demethylation activity of the rest of JmjC-containing proteins and their activity on additional substrates will be identified upon the availability of technologies such as specific antibodies and sensitive mass spectrometry. The enzymes are highly expressed during the hematopoietic development and may play an important role in higher animals and humans. Currently, the vast majority of the identified biological functions of the JmjC-containing proteins are attributed to their KDM activity. Figure 1 View largeDownload slide 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. Figure 1 View largeDownload slide 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. While arginine methyl transferases have been identified and their function in cells have been well documented (Yang and Bedford, 2013; Fuhrmann et al., 2015), RDMs have not yet been identified. Jmjc domain-containing 6 (JMJD6) was previously reported as a putative RDM for asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) histone substrates H3 and H4 (Chang et al., 2007). However, this function was subjected to conflicting reports. Two follow-up reports indicated that JMJD6 only catalyses 2OG-dependent C-5 hydroxylation of lysine residues in mRNA splicing-regulatory proteins and histones (Webby et al., 2009; Mantri et al., 2010). More recently, a study showed that certain KDMs possess RDM activity on methylated histone peptide model substrates (Walport et al., 2016) (Figure 1C). The catalytic mechanism for JmjC proteins is catalyzing hydroxylation of C–H bonds and N-demethylation via hydroxylation (Figure 1D). The active site Fe(II) is bound by HXD/E…H and cofactor 2OG. In the absence of substrates, 2OG-dependent oxygenases often catalyze a slow, uncoupled reaction in which 2OG is decarboxylated to form succinate, carbon dioxide, and a reactive Fe(IV)=O ferryl intermediate. Addition of substrates in the reaction will dramatically stimulate the process. This iron(IV)-oxo intermediate then oxidizes the C–H bond and leads to formation of a hydroxylated product. If the hydroxylation happens on methyl group on an amidogen, this process will form an unstable hemiaminal. The hydroxymethyl is likely spontaneously released as formaldehyde, resulting in a demethylated substrate. The process does not discriminate the methylarginine from methylysine. Hydroxylation is an intermediate step of demethylation. It has been reported recently that two orphan JmjC-containing proteins, JMJD5 and JMJD7, have divalent cation-dependent protease activities that preferentially cleave the tails of histone 3 or 4 containing methylated lysine or arginine (Figure 1C). After the initial specific cleavage, JMJD5 and JMJD7, acting as aminopeptidases, progressively digest the C-terminal products, which is a methylation-dependent peptidase activity and also termed as clipping (Liu et al., 2017; Shen et al., 2017). Among 23 JmjC domain-containing proteins with crystal structures, most of them contain Zn2+ besides Fe2+, which increases the possibility for JmjC-containing proteins to act as methyl group-dependent metalloproteases. The orphan subfamily members such as JMJD5 only have two residues to coordinate Zn2+, which could be flexible for peptidase reaction, similarly to the ones in metalloproteases. In contrast, the members in PHF2/PHF8 and JMJD2/JHDM3 subfamilies have four residues to coordinate Zn2+, which is rigid, buried, and not accessible to the substrate. For the JARID and UTX/UTY subfamilies, Zn2+ is far away from Fe(II) catalysis center, which makes it difficult for a coordinated reaction between methyl group recognition and clipping. Further experiments are warranted to test whether the status of Zn2+ in proteins is a determining factor for such a cleavage. The biological significance of such a reaction is not clear yet but could be involved in transcriptional regulation, DNA damage response, and apoptosis in order to rapidly deplete the histones and remodel the chromatin structure to expose DNA for the necessary reactions. [This work was supported by NCI/NIH R01CA073764.] References Chang , B. , Chen , Y. , Zhao , Y. , et al. . ( 2007 ). JMJD6 is a histone arginine demethylase . Science 318 , 444 – 447 . Google Scholar Crossref Search ADS PubMed Fuhrmann , J. , Clancy , K.W. , and Thompson , P.R. ( 2015 ). Chemical biology of protein arginine modifications in epigenetic regulation . Chem. Rev. 115 , 5413 – 5461 . Google Scholar Crossref Search ADS PubMed Klose , R.J. , Kallin , E.M. , and Zhang , Y. ( 2006 ). JmjC-domain-containing proteins and histone demethylation . Nat. Rev. Genet. 7 , 715 – 727 . Google Scholar Crossref Search ADS PubMed Liu , H. , Wang , C. , Lee , S. , et al. . ( 2017 ). Clipping of arginine-methylated histone tails by JMJD5 and JMJD7 . Proc. Natl Acad. Sci. USA 114 , E7717 – E7726 . Google Scholar Crossref Search ADS Mantri , M. , Krojer , T. , Bagg , E.A. , et al. . ( 2010 ). Crystal structure of the 2-oxoglutarate- and Fe(II)-dependent lysyl hydroxylase JMJD6 . J. Mol. Biol. 401 , 211 – 222 . Google Scholar Crossref Search ADS PubMed Shen , J. , Xiang , X. , Chen , L. , et al. . ( 2017 ). JMJD5 cleaves monomethylated histone H3 N-tail under DNA damaging stress . EMBO Rep. 18 , 2131 – 2143 . Google Scholar Crossref Search ADS PubMed Walport , L.J. , Hopkinson , R.J. , Chowdhury , R. , et al. . ( 2016 ). Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases . Nat. Commun. 7 , 11974 . Google Scholar Crossref Search ADS PubMed Webby , C.J. , Wolf , A. , Gromak , N. , et al. . ( 2009 ). Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing . Science 325 , 90 – 93 . Google Scholar Crossref Search ADS PubMed Yang , Y. , and Bedford , M.T. ( 2013 ). Protein arginine methyltransferases and cancer . Nat. Rev. Cancer 13 , 37 – 50 . Google Scholar Crossref Search ADS PubMed © The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Molecular Cell Biology Oxford University Press

Jumonji domain-containing protein family: the functions beyond lysine demethylation

Loading next page...
 
/lp/ou_press/jumonji-domain-containing-protein-family-the-functions-beyond-lysine-ueISTV47rG
Publisher
Oxford University Press
Copyright
© The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
ISSN
1674-2788
eISSN
1759-4685
D.O.I.
10.1093/jmcb/mjy010
Publisher site
See Article on Publisher Site

Abstract

Two of the unsolved but important questions in epigenetics are whether arginine demethylases (RDMs) exist and whether proteolytic cleavage of the histone tails and subsequent histone remodeling are a major epigenetic modification process. Jumonji domain (JmjC)-containing proteins have been characterized as lysine demethylases (KDMs) in a certain degree (Klose et al., 2006). Emerging evidences indicate that they also catalyze demethylation reaction on the arginine residues and proteolytic removal of histone tails. These processes are likely associated with biological meanings. This research highlight is intended to provide a bird’s eye view of the current state of the expanded biochemical properties of JmjC-containing proteins as RDMs and methylation-dependent histone tail clipping enzymes. The JmjC-containing proteins are a family of non-haeme iron(II) and 2-oxoglutarate (2OG or α-ketoglutarate)-dependent oxygenases with a characteristic double-stranded and antiparallel β-sheet structure. An example of JMJD5 (PDB 4gjy) is shown in Figure 1A. Our comprehensive three-dimensional (3D) structural alignment of available crystal structures of 23 JmjC-containing proteins indicates that previously identified asparate/glutamate and two histone residues coordinate the iron(II) cofactor, while two aromatic ring-containing residues (W, Y, or F) play a critical role in stabilizing both iron(II) and the catalytic pocket with π-cation interactions (Figure 1A). The family has been classified into seven subfamilies based on their sequences (Klose et al., 2006). Our 3D structural alignment with TM-score heatmap confirms such clustering (Figure 1B). A new family member, TYW5, which may fit into the orphan subfamily has been identified during our recent search (Figure 1C). So far, 22 out of 31 family members have been reported to possess a KDM activity on the sites K4, K9, K27, and K36 of histone 3 as well as non-histone substrates in mono-, di-, and tri-methylation forms (Figure 1C). It is predictable that the demethylation activity of the rest of JmjC-containing proteins and their activity on additional substrates will be identified upon the availability of technologies such as specific antibodies and sensitive mass spectrometry. The enzymes are highly expressed during the hematopoietic development and may play an important role in higher animals and humans. Currently, the vast majority of the identified biological functions of the JmjC-containing proteins are attributed to their KDM activity. Figure 1 View largeDownload slide 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. Figure 1 View largeDownload slide 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. While arginine methyl transferases have been identified and their function in cells have been well documented (Yang and Bedford, 2013; Fuhrmann et al., 2015), RDMs have not yet been identified. Jmjc domain-containing 6 (JMJD6) was previously reported as a putative RDM for asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) histone substrates H3 and H4 (Chang et al., 2007). However, this function was subjected to conflicting reports. Two follow-up reports indicated that JMJD6 only catalyses 2OG-dependent C-5 hydroxylation of lysine residues in mRNA splicing-regulatory proteins and histones (Webby et al., 2009; Mantri et al., 2010). More recently, a study showed that certain KDMs possess RDM activity on methylated histone peptide model substrates (Walport et al., 2016) (Figure 1C). The catalytic mechanism for JmjC proteins is catalyzing hydroxylation of C–H bonds and N-demethylation via hydroxylation (Figure 1D). The active site Fe(II) is bound by HXD/E…H and cofactor 2OG. In the absence of substrates, 2OG-dependent oxygenases often catalyze a slow, uncoupled reaction in which 2OG is decarboxylated to form succinate, carbon dioxide, and a reactive Fe(IV)=O ferryl intermediate. Addition of substrates in the reaction will dramatically stimulate the process. This iron(IV)-oxo intermediate then oxidizes the C–H bond and leads to formation of a hydroxylated product. If the hydroxylation happens on methyl group on an amidogen, this process will form an unstable hemiaminal. The hydroxymethyl is likely spontaneously released as formaldehyde, resulting in a demethylated substrate. The process does not discriminate the methylarginine from methylysine. Hydroxylation is an intermediate step of demethylation. It has been reported recently that two orphan JmjC-containing proteins, JMJD5 and JMJD7, have divalent cation-dependent protease activities that preferentially cleave the tails of histone 3 or 4 containing methylated lysine or arginine (Figure 1C). After the initial specific cleavage, JMJD5 and JMJD7, acting as aminopeptidases, progressively digest the C-terminal products, which is a methylation-dependent peptidase activity and also termed as clipping (Liu et al., 2017; Shen et al., 2017). Among 23 JmjC domain-containing proteins with crystal structures, most of them contain Zn2+ besides Fe2+, which increases the possibility for JmjC-containing proteins to act as methyl group-dependent metalloproteases. The orphan subfamily members such as JMJD5 only have two residues to coordinate Zn2+, which could be flexible for peptidase reaction, similarly to the ones in metalloproteases. In contrast, the members in PHF2/PHF8 and JMJD2/JHDM3 subfamilies have four residues to coordinate Zn2+, which is rigid, buried, and not accessible to the substrate. For the JARID and UTX/UTY subfamilies, Zn2+ is far away from Fe(II) catalysis center, which makes it difficult for a coordinated reaction between methyl group recognition and clipping. Further experiments are warranted to test whether the status of Zn2+ in proteins is a determining factor for such a cleavage. The biological significance of such a reaction is not clear yet but could be involved in transcriptional regulation, DNA damage response, and apoptosis in order to rapidly deplete the histones and remodel the chromatin structure to expose DNA for the necessary reactions. [This work was supported by NCI/NIH R01CA073764.] References Chang , B. , Chen , Y. , Zhao , Y. , et al. . ( 2007 ). JMJD6 is a histone arginine demethylase . Science 318 , 444 – 447 . Google Scholar Crossref Search ADS PubMed Fuhrmann , J. , Clancy , K.W. , and Thompson , P.R. ( 2015 ). Chemical biology of protein arginine modifications in epigenetic regulation . Chem. Rev. 115 , 5413 – 5461 . Google Scholar Crossref Search ADS PubMed Klose , R.J. , Kallin , E.M. , and Zhang , Y. ( 2006 ). JmjC-domain-containing proteins and histone demethylation . Nat. Rev. Genet. 7 , 715 – 727 . Google Scholar Crossref Search ADS PubMed Liu , H. , Wang , C. , Lee , S. , et al. . ( 2017 ). Clipping of arginine-methylated histone tails by JMJD5 and JMJD7 . Proc. Natl Acad. Sci. USA 114 , E7717 – E7726 . Google Scholar Crossref Search ADS Mantri , M. , Krojer , T. , Bagg , E.A. , et al. . ( 2010 ). Crystal structure of the 2-oxoglutarate- and Fe(II)-dependent lysyl hydroxylase JMJD6 . J. Mol. Biol. 401 , 211 – 222 . Google Scholar Crossref Search ADS PubMed Shen , J. , Xiang , X. , Chen , L. , et al. . ( 2017 ). JMJD5 cleaves monomethylated histone H3 N-tail under DNA damaging stress . EMBO Rep. 18 , 2131 – 2143 . Google Scholar Crossref Search ADS PubMed Walport , L.J. , Hopkinson , R.J. , Chowdhury , R. , et al. . ( 2016 ). Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases . Nat. Commun. 7 , 11974 . Google Scholar Crossref Search ADS PubMed Webby , C.J. , Wolf , A. , Gromak , N. , et al. . ( 2009 ). Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing . Science 325 , 90 – 93 . Google Scholar Crossref Search ADS PubMed Yang , Y. , and Bedford , M.T. ( 2013 ). Protein arginine methyltransferases and cancer . Nat. Rev. Cancer 13 , 37 – 50 . Google Scholar Crossref Search ADS PubMed © The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Journal of Molecular Cell BiologyOxford University Press

Published: Aug 1, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off