A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes.

[kabuki syndrome]

The mixed lineage leukemia -1 (MLL 1 ) enzyme is a histone H 3 lysine 4 (H 3 K 4 ) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human SET 1 family of enzymes that include MLL 1 -MLL 4 and SETd 1 a ,b . Dimethylation of H 3 K 4 requires a sub-complex including WRAD (WDR 5 , RbBP 5 , Ash 2 L , and DPY-30 ), which binds to each SET 1 family member forming a minimal core complex that is required for multiple lysine methylation . We recently demonstrated that WRAD is a novel histone methyltransferase that preferentially catalyzes H 3 K 4 dimethylation in a manner that is dependent on an unknown non-active-site surface from the MLL 1 SET domain . Recent genome sequencing studies have identified a number of human disease-associated missense mutations that localize to the SET domains of several MLL family members . In this investigation , we mapped many of these mutations onto the three -dimensional structure of the SET domain and noticed that a subset of MLL 2 (KMT 2 D , ALR , MLL 4 )-associated Kabuki syndrome missense mutations map to a common solvent-exposed surface that is not expected to alter enzymatic activity . We introduced these mutations into the MLL 1 SET domain and observed that all are defective for H 3 K 4 dimethylation by the MLL 1 core complex , which is associated with a loss of the ability of MLL 1 to interact with WRAD or with the RbBP 5 /Ash 2 L heterodimer . Our results suggest that amino acids from this surface , which we term the Kabuki interaction surface or KIS , are required for formation of a second active site within SET 1 family core complexes .

Diseases
Validation

Diseases presenting "second active site" symptom

kabuki syndrome

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