Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal
Poly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromat...
| Asıl Yazarlar: | , , , , , , , , , , , , , |
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| Materyal Türü: | Journal article |
| Dil: | English |
| Baskı/Yayın Bilgisi: |
Springer Nature
2021
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| _version_ | 1826307374912110592 |
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| author | Rack, JGM Liu, Q Zorzini, V Voorneveld, J Ariza, A Honarmand Ebrahimi, K Reber, JM Krassnig, SC Ahel, D van der Marel, GA Mangerich, A McCullagh, JSO Filippov, DV Ahel, I |
| author_facet | Rack, JGM Liu, Q Zorzini, V Voorneveld, J Ariza, A Honarmand Ebrahimi, K Reber, JM Krassnig, SC Ahel, D van der Marel, GA Mangerich, A McCullagh, JSO Filippov, DV Ahel, I |
| author_sort | Rack, JGM |
| collection | OXFORD |
| description | Poly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromatin structure and Wnt signalling. Despite decades of research, the principles and mechanisms underlying all steps of PAR removal remain actively studied. In this work, we synthesise well-defined PAR branch point molecules and demonstrate that PARG, but not ARH3, can resolve this distinct PAR architecture. Structural analysis of ARH3 in complex with dimeric ADP-ribose as well as an ADP-ribosylated peptide reveal the molecular basis for the hydrolysis of linear and terminal ADP-ribose linkages. We find that ARH3-dependent hydrolysis requires both rearrangement of a catalytic glutamate and induction of an unusual, square-pyramidal magnesium coordination geometry. |
| first_indexed | 2024-03-07T07:02:09Z |
| format | Journal article |
| id | oxford-uuid:ffdc9e17-cd69-439c-993d-f66052ae65d4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:02:09Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:ffdc9e17-cd69-439c-993d-f66052ae65d42022-03-27T13:48:20ZMechanistic insights into the three steps of poly(ADP-ribosylation) reversalJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ffdc9e17-cd69-439c-993d-f66052ae65d4EnglishSymplectic ElementsSpringer Nature2021Rack, JGMLiu, QZorzini, VVoorneveld, JAriza, AHonarmand Ebrahimi, KReber, JMKrassnig, SCAhel, Dvan der Marel, GAMangerich, AMcCullagh, JSOFilippov, DVAhel, IPoly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromatin structure and Wnt signalling. Despite decades of research, the principles and mechanisms underlying all steps of PAR removal remain actively studied. In this work, we synthesise well-defined PAR branch point molecules and demonstrate that PARG, but not ARH3, can resolve this distinct PAR architecture. Structural analysis of ARH3 in complex with dimeric ADP-ribose as well as an ADP-ribosylated peptide reveal the molecular basis for the hydrolysis of linear and terminal ADP-ribose linkages. We find that ARH3-dependent hydrolysis requires both rearrangement of a catalytic glutamate and induction of an unusual, square-pyramidal magnesium coordination geometry. |
| spellingShingle | Rack, JGM Liu, Q Zorzini, V Voorneveld, J Ariza, A Honarmand Ebrahimi, K Reber, JM Krassnig, SC Ahel, D van der Marel, GA Mangerich, A McCullagh, JSO Filippov, DV Ahel, I Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal |
| title | Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal |
| title_full | Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal |
| title_fullStr | Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal |
| title_full_unstemmed | Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal |
| title_short | Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal |
| title_sort | mechanistic insights into the three steps of poly adp ribosylation reversal |
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