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Molecular and Cellular Biology, January 2008, p. 269-281, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01077-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Role of the PLDLS-Binding Cleft Region of CtBP1 in Recruitment of Core and Auxiliary Components of the Corepressor Complex{triangledown}

M. Kuppuswamy,1 S. Vijayalingam,1 Ling-Jun Zhao,1 Yun Zhou,1,{dagger} T. Subramanian,1 Jan Ryerse,2 and G. Chinnadurai1*

Institute for Molecular Virology, Saint Louis University School of Medicine, Daisy Research Center, 1100 South Grand Blvd., St. Louis, Missouri 63104,1 Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, Missouri 631042

Received 18 June 2007/ Returned for modification 20 July 2007/ Accepted 14 October 2007

C-terminal binding protein (CtBP) family proteins CtBP1 and CtBP2 are highly homologous transcriptional corepressors and are recruited by a large number of transcription factors to mediate sequence-specific transcriptional repression. In addition to DNA-binding repressors, the nuclear protein complex of CtBP1 consists of enzymatic constituents such as histone deacetylases (HDAC1/2), histone methyl transferases (HMTases; G9a and GLP), and the lysine-specific demethylase (LSD1). Additionally, CtBPs also recruit the components of the sumoylation machinery. The CtBPs contain two different unique structural elements, a hydrophobic cleft, with which factors that contain motifs related to the E1A PLDLS motif bind, and a surface groove that binds with factors containing motifs related to the sequence RRTGXPPXL (RRT motif). By structure-based functional dissection of CtBP1, we show that the PLDLS-binding cleft region functions as the primary recruitment center for DNA-binding factors and for the core and auxiliary enzymatic constituents of the CtBP1 corepressor complex. We identify HDAC1/2, CoREST/LSD1, and Ubc9 (E2) as the core constituents of the CtBP1 complex, and these components interact with the PLDLS cleft region through non-PLDLS interactions. Among the CtBP core constituents, HDACs contribute predominantly to the repression activity of CtBP1. The auxiliary components include an HMTase complex (G9a/Wiz/CDYL) and two SUMO E3 ligases, HPC2 and PIAS1. The interaction of auxiliary components with CtBP1 is excluded by PLDLS (E1A)-mediated interactions. Although monomeric CtBP1 is proficient in the recruiting of both core and auxiliary components, NAD(H)-dependent dimerization is required for transcriptional repression. We also provide evidence that CtBP1 functions as a platform for sumoylation of cofactors.

* Corresponding author. Mailing address: Institute for Molecular Virology, Saint Louis University School of Medicine, Daisy Research Center, 1100 South Grand Blvd., St. Louis, MO 63104. Phone: (314) 977-8794. Fax: (314) 977-8798. E-mail: chinnag{at}slu.edu.

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Present Address: Department of Pharmacology, Case Western University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106.

Molecular and Cellular Biology, January 2008, p. 269-281, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01077-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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