Differential regulation of the two transcriptional activation domains of the coiled-coil coactivator CoCoA by sumoylation.
BACKGROUND
The coiled-coil coactivator (CoCoA) enhances transcriptional activity of nuclear receptors, the xenobiotic aryl hydrocarbon receptor, and the lymphocyte enhancer factors (LEF) in the Wnt/beta-catenin signaling pathway. CoCoA is comprised of a large central coiled coil domain flanked by N-terminal and C-terminal activation domains (AD). The N-terminal AD of CoCoA is required for coactivator function with LEF and beta-catenin, while the C-terminal AD of CoCoA is required for coactivator function with nuclear receptors. We explored the role of sumoylation in regulating the activities of the two ADs and the coactivator function of CoCoA.


RESULTS
The N-terminus of CoCoA is covalently modified by SUMO1 at Lys-29; both PIAS1 and ARIP3 function as E3 ligases. Fusion of SUMO1 to the N-terminus (mimicking sumoylation) reduced coactivator function of CoCoA with LEF1 and the activity of the N-terminal AD. The N- and C-termini of CoCoA can bind to each other, and C-terminal transactivation activity is attenuated in the presence of the N-terminus, indicating that the N-C interaction regulates the activity of the C-terminal AD. Fusion of SUMO1 to the N-terminal fragment of CoCoA reduced the N-C interaction and inhibition of C-terminal AD activity by the N-terminal fragment.


CONCLUSIONS
Sumoylation of CoCoA differentially regulates the coactivator activity of CoCoA with nuclear receptors versus LEF1, by attenuating the N-terminal AD activity and enhancing the activity of the C-terminal AD.
Yang
Catherine K
CK
Department of Biochemistry and Molecular Biology and the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089-9176, USA. catherinekyang@gmail.com
Kim
Jeong Hoon
JH
Ann
David K
DK
Stallcup
Michael R
MR
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*; D015533:Transcriptional Activation
D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins; D015534:Trans-Activators