| Primary Identifier | IPR025789 | Type | Domain |
| Short Name | DOT1_dom |
| description | This entry represents the DOT1 domain.The Dot1 protein (Dot1p) is an histone-lysine N-methyltransferase (EC2.1.1.43) that methylates lysine 79 (Lys-79) of histone H3. It was firstidentified as a Disruptor Of Telomeric silencing in yeast where Dot1p isimplicated in gene silencing and localization of the Silent InformationRegulator (SIR) complex; in higher eukaryotes the methylation carried out bythis enzyme may be used for differentiating chromatin domains. Unlike otherhistone-lysine methyltransferases (HKMTs), Dot1p displays a Rossmann-like(Class I) S-adenosyl-L-methyionine (SAM)-dependent MT foldwhile other HKMTs contain the SET domain and hence belong toa whole different structural class [, ].Whereas most HKMTs, such as Suvar3-9 methylate Lys on the N-terminal tails ofhistones that stick out from the nucleosome, Dot1p substrate (Lys-79 ofhistone H3) is located in the conserved histone core, in a short turnconnecting the first and second helices, exposed on the nucleosome disksurface [, ]. In order for Lys-79 of H3 to be methylated by Dot1p, anotherlysine, Lys-123 of histone H2B, needs to be ubiquitinated. A possible reasonput forward for this requirement is that the ubiquitination may create a spacebetween adjacent nucleosomes, permitting access of Dot1p to its substrate[, ]. In yeast, different states of methylation on Lys-79 of histone H3(unmodified, mono-, di- and trimethylated) co-exist at the same time, but noclear function is associated with these different methylation states [].The strucure of the evolutionary conserved core of Dot1p, the DOT1 domain, hasfirst been described for the yeast Dot1p in complex withS-adenosyl-L-homocysteine (AdoHcy) and then for the humanDot1-like protein (Dot1Lp) in complex with SAM. The DOT1domain is about 300-350 amino acids long and is usually located at either ofthe extremities of the protein sequence: it stands at the C terminus of theyeast Dot1p and at the N terminus of the human Dot1Lp [, ]. DOT1 displays arather elongated structure and can be subdivided into two parts: the N- andthe C-terminal subdomains []. The N-terminal part is made up of five alphahelices and two pairs of short beta strand hairpins. The C-terminal partdisplays a Rossmann-like fold: it consists in aseven-stranded beta sheet tucked by five alpha helices (three helices on oneside of the sheet and two on the other), the sheet contains a centraltopological switchpoint resulting in a deep pocket where SAM is bound. The twosubdomains are linked covalently by a loop. Altogether the SAM binding pocketis formed by five segments of the DOT1 domain of which four are located in theC-terminal substructure of the DOT1 domain and one in the loop connecting bothparts; two of these segments are conserved across different Class ISAM-dependent MTs []. |
