A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases.
The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silencing, genomic stability and regulation of replication. We present the structure of the histone H4K20 methyltransferase Suv4-20h2 in complex with its histone H4 peptide substrate and S-adenosyl methionine cofactor. Analysis of the structure reveals that the Suv4-20h2 active site diverges from the canonical SET domain configuration and generates a high degree of both substrate and product specificity. Together with supporting biochemical data comparing Suv4-20h1 and Suv4-20h2, we demonstrate that the Suv4-20 family enzymes take a previously mono-methylated H4K20 substrate and generate an exclusively di-methylated product. We therefore predict that other enzymes are responsible for the tri-methylation of histone H4K20 that marks silenced heterochromatin.
Division of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK.
Stacey M
SM
Southall
Nora B
NB
Cronin
Jon R
JR
Wilson
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D029721:Drosophila Proteins; D006657:Histones; C570043:Suv4-20h protein, mouse; D012436:S-Adenosylmethionine; C487546:Hmt4-20 protein, Drosophila; D011495:Histone-Lysine N-Methyltransferase