Coactivator-associated arginine methyltransferase 1 (CARM1), a protein arginine methyltransferase recruited by several transcription factors, methylates a large variety of proteins and plays a critical role in gene expression. We report, in this paper, four crystal structures of isolated modules of CARM1. The 1.7 Å crystal structure of the N-terminal domain of CARM1 reveals an unexpected PH domain, a scaffold frequently found to regulate protein-protein interactions in a large variety of biological processes. Three crystal structures of the CARM1 catalytic module, two free and one cofactor-bound forms (refined at 2.55 Å , 2.4 Å and 2.2 Å , respectively) reveal large structural modifications including disorder to order transition, helix to strand transition and active site modifications. The N-terminal and the C-terminal end of CARM1 catalytic module contain molecular switches that may inspire how CARM1 regulates its biological activities by protein-protein interactions.

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Coactivator-associated arginine methyltransferase 1 (CARM1) plays a crucial role in gene expression as a coactivator of several nuclear hormone receptors and also of non-nuclear receptor systems. Its recruitment by the transcriptional machinery induces protein methylation, leading to chromatin remodelling and gene activation. CARM1 and two structural states of CARM1 140-480 were expressed, purified and crystallized. Crystals of CARM1 28-507 belong to space group P6 2 22, with unit-cell parameters a = b = 136.0, c = 125.3 Å ; they diffract to beyond 2.5 Å resolution using synchrotron radiation and contain one monomer in the asymmetric unit. The structure of CARM1 28-507 was solved by multiple isomorphous replacement and anomalous scattering methods. Crystals of apo CARM1 140-480 belong to space group I222, with unit-cell parameters a = 74.6, b = 99.0, c = 207.4 Å ; they diffract to beyond 2.7 Å resolution and contain two monomers in the asymmetric unit. Crystals of CARM1 140-480 in complex with S-adenosyl-l-homocysteine belong to space P2 1 2 1 2, with unit-cell parameters a = 74.6, b = 98.65, c = 206.08 Å ; they diffract to beyond 2.6 Å resolution and contain four monomers in the asymmetric unit. The structures of apo and holo CARM1 140-480 were solved by molecular-replacement techniques from the structure of CARM1 .

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