title: Identifying Family-Member-Specific Targets of Mono-ARTDs by Using a Chemical Genetics Approach.
abstract: ADP-ribosyltransferases (ARTD1-16) have emerged as major downstream effectors of NAD(+) signaling in the cell. Most ARTDs (ARTD7 and 8, 10-12, and 14-17) catalyze the transfer of a single unit of ADP-ribose from NAD(+) to target proteins, a process known as mono-ADP-ribosylation (MARylation). Progress in understanding the cellular functions of MARylation has been limited by the inability to identify the direct targets for individual mono-ARTDs. Here, we engineered mono-ARTDs to use an NAD(+) analog that is orthogonal to wild-type ARTDs. We profiled the MARylomes of ARTD10 and ARTD11 in vitro, identifying isoform-specific targets and revealing a potential role for ARTD11 in nuclear pore complex biology. We found that ARTD11 targeting is dependent on both its regulatory and catalytic domains, which has important implications for how ARTDs recognize their targets. We anticipate that our chemical genetic strategy will be generalizable to all mono-ARTD family members based on the similarity of the mono-ARTD catalytic domains.
authors.affiliation: Program in Chemical Biology and Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97210, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Carter-O'Connell
authors.affiliation: Program in Chemical Biology and Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97210, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Jin
authors.affiliation: Program in Chemical Biology and Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97210, USA.
authors.forename: Rory K
authors.initials: RK
authors.lastname: Morgan
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
authors.forename: Roko
authors.initials: R
authors.lastname: Zaja
authors.affiliation: Department of Biochemistry, Oregon Health and Science University, Portland, OR 97210, USA.
authors.forename: Larry L
authors.initials: LL
authors.lastname: David
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ahel
authors.affiliation: Program in Chemical Biology and Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97210, USA. Electronic address: cohenmic@ohsu.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cohen
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002851:Chromatography, High Pressure Liquid; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009243:NAD / Q000031:analogs & derivatives / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D009243:NAD; D036002:ADP Ribose Transferases; D017346:Protein Serine-Threonine Kinases; C110522:SRPK2 protein, human