Multipurpose MRG domain involved in cell senescence and proliferation exhibits structural homology to a DNA-interacting domain.
The ubiquitous MRG/MORF family of proteins is involved in cell senescence, or the terminal loss of proliferative potential, a model for aging and tumor suppression at the cellular level. These proteins are defined by the approximately 20 kDa MRG domain that binds a plethora of transcriptional regulators and chromatin-remodeling factors, including the histone deacetylase transcriptional corepressor mSin3A and the novel nuclear protein PAM14, and they are also known components of the Tip60/NuA4 complex via interactions with the MRG binding protein (MRGBP). We present here the crystal structure of a prototypic MRG domain from human MRG15 whose core consists of two orthogonal helix hairpins. Despite the lack of sequence similarity, the core structure has surprisingly striking homology to a DNA-interacting domain of the tyrosine site-specific recombinases XerD, lambda integrase, and Cre. Site-directed mutagenesis studies based on the X-ray structure and bioinformatics identified key residues involved in the binding of PAM14 and MRGBP.
Bowman
Brian R
BR
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Moure
Carmen M
CM
Kirtane
Bhakti M
BM
Welschhans
Robert L
RL
Tominaga
Kaoru
K
Pereira-Smith
Olivia M
OM
Quiocho
Florante A
FA
D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D051548:Histone Acetyltransferases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary / Q000235:genetics; D040681:Structural Homology, Protein; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C470833:MORF4L1 protein, human; C439067:MRFAP1 protein, human; C479739:MRGBP protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D051548:Histone Acetyltransferases