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Molecular and Cellular Biology, November 2004, p. 9274-9285, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9274-9285.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

FF Domains of CA150 Bind Transcription and Splicing Factors through Multiple Weak Interactions

Matthew J. Smith,1,2 Sarang Kulkarni,1 and Tony Pawson1,2*

Samuel Lunenfeld Research Institute, Mount Sinai Hospital,1 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada2

Received 21 April 2004/ Returned for modification 19 May 2004/ Accepted 11 August 2004

The human transcription factor CA150 modulates human immunodeficiency virus type 1 gene transcription and contains numerous signaling elements, including six FF domains. Repeated FF domains are present in several transcription and splicing factors and can recognize phosphoserine motifs in the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Using mass spectrometry, we identify a number of nuclear binding partners for the CA150 FF domains and demonstrate a direct interaction between CA150 and Tat-SF1, a protein involved in the coupling of splicing and transcription. CA150 FF domains recognize multiple sites within the Tat-SF1 protein conforming to the consensus motif (D/E)2/5-F/W/Y-(D/E)2/5. Individual FF domains are capable of interacting with Tat-SF1 peptide ligands in an equivalent and noncooperative manner, with affinities ranging from 150 to 500 µM. Repeated FF domains therefore appear to bind their targets through multiple weak interactions with motifs comprised of negatively charged residues flanking aromatic amino acids. The RNAPII CTD represents a consensus FF domain-binding site, contingent on generation of the requisite negative charges by phosphorylation of serines 2 and 5. We propose that CA150, through the dual recognition of acidic motifs in proteins such as Tat-SF1 and the phosphorylated CTD, could mediate the recruitment of transcription and splicing factors to actively transcribing RNAPII.

* Corresponding author. Mailing address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario, Canada, M5G 1X5. Phone: (416) 586-8262. Fax: (416) 586-8869. E-mail: pawson{at}mshri.on.ca.

Molecular and Cellular Biology, November 2004, p. 9274-9285, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9274-9285.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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