title: Structural and functional roles of Daxx SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation.
abstract: Small ubiquitin-like modifier (SUMO) conjugation and interaction are increasingly associated with various cellular processes. However, little is known about the cellular signaling mechanisms that regulate proteins for distinct SUMO paralog conjugation and interactions. Using the transcriptional coregulator Daxx as a model, we show that SUMO paralog-selective binding and conjugation are regulated by phosphorylation of the Daxx SUMO-interacting motif (SIM). NMR structural studies show that Daxx (732)E-I-I-V-L-S-D-S-D(740) is a bona fide SIM that binds to SUMO-1 in a parallel orientation. Daxx-SIM is phosphorylated by CK2 kinase at residues S737 and S739. Phosphorylation promotes Daxx-SIM binding affinity toward SUMO-1 over SUMO-2/3, causing Daxx preference for SUMO-1 conjugation and interaction with SUMO-1-modified factors. Furthermore, Daxx-SIM phosphorylation enhances Daxx to sensitize stress-induced cell apoptosis via antiapoptotic gene repression. Our findings provide structural insights into the Daxx-SIM:SUMO-1 complex, a model of SIM phosphorylation-enhanced SUMO paralog-selective modification and interaction, and phosphorylation-regulated Daxx function in apoptosis.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Che-Chang
authors.initials: CC
authors.lastname: Chang
authors.forename: Mandar T
authors.initials: MT
authors.lastname: Naik
authors.forename: Yen-Sung
authors.initials: YS
authors.lastname: Huang
authors.forename: Jen-Chong
authors.initials: JC
authors.lastname: Jeng
authors.forename: Pei-Hsin
authors.initials: PH
authors.lastname: Liao
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Kuo
authors.forename: Chun-Chen
authors.initials: CC
authors.lastname: Ho
authors.forename: Yung-Lin
authors.initials: YL
authors.lastname: Hsieh
authors.forename: Chiou-Hong
authors.initials: CH
authors.lastname: Lin
authors.forename: Nai-Jia
authors.initials: NJ
authors.lastname: Huang
authors.forename: Nandita M
authors.initials: NM
authors.lastname: Naik
authors.forename: Camy C-H
authors.initials: CC
authors.lastname: Kung
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Lin
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
authors.forename: Kun-Sang
authors.initials: KS
authors.lastname: Chang
authors.forename: Tai-Huang
authors.initials: TH
authors.lastname: Huang
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047390:Casein Kinase II / Q000378:metabolism; D002460:Cell Line; D056970:Co-Repressor Proteins; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025842:SUMO-1 Protein / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D047390:Casein Kinase II