Molecular Basis for the Mechanism of Constitutive CBP/p300 Coactivator Recruitment by CRTC1-MAML2 and Its Implications in cAMP Signaling.
The cyclic AMP response element-binding protein (CREB) is a signal-dependent transcription factor that exerts its positive effects on gene transcription of a broad range of genes by recruiting coactivators, including CREB-binding protein (CBP), its paralog, p300, and the family of CRTC (CREB-regulated transcriptional coactivators) proteins. Whereas recruitment of CBP/p300 is dependent on CREB phosphorylation at Ser133, recruitment of CRTCs is not. Here we describe how both mechanisms could concurrently drive transcription of CREB targets in a subset of head and neck cancers featuring chromosomal translocations that fuse portions of CRTC1 and CRTC3 genes with that of the Mastermind-like transcriptional coactivator MAML2. We show that a peptide derived from transactivation domain 1 (TAD1) of MAML2 binds to the CBP KIX domain with micromolar affinity. An ∼20-residue segment within this peptide, conserved in MAML2 orthologs and paralogs, binds directly to a KIX surface previously shown to bind to MLL1. The 20-residue MAML2 segment shares sequence similarity with MLL1, especially at those positions in direct contact with KIX, and like MLL1, the segment is characterized by the presence of an ∼10-residue helix. Because CRTC1/3-MAML2 fusion proteins are constitutively nuclear, like CREB, our results suggest constitutive recruitment of CBP/p300 to CREB targets that could be further enhanced by signals that cause CREB Ser133 phosphorylation.
Department of Molecular Biosciences, Northwestern University , 2205 Tech Drive, Evanston, Illinois 60208-3500, United States.
Michael David
MD
Clark
Department of Molecular Biosciences, Northwestern University , 2205 Tech Drive, Evanston, Illinois 60208-3500, United States.
Ganesan Senthil
GS
Kumar
Department of Molecular Biosciences, Northwestern University , 2205 Tech Drive, Evanston, Illinois 60208-3500, United States.
Ryan
R
Marcum
Department of Molecular Biosciences, Northwestern University , 2205 Tech Drive, Evanston, Illinois 60208-3500, United States.
Qianyi
Q
Luo
Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
Yongbo
Y
Zhang
Department of Molecular Biosciences, Northwestern University , 2205 Tech Drive, Evanston, Illinois 60208-3500, United States.
Ishwar
I
Radhakrishnan
D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000378:metabolism*
C519509:Crtc1 protein, mouse; C467909:MAML2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000242:Cyclic AMP; D050880:p300-CBP Transcription Factors