The Human Mixed Lineage Leukemia 5 (MLL5), a Sequentially and Structurally Divergent SET Domain-Containing Protein with No Intrinsic Catalytic Activity

Abstract

Mixed Lineage Leukemia 5 (MLL5) plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. Chromatin binding is ensured by its plant homeodomain (PHD) through a direct interaction with the N-terminus of histone H3 (H3). In addition, MLL5 contains a Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain, a protein module that usually displays histone lysine methyltransferase activity. We report here the crystal structure of the unliganded SET domain of human MLL5 at 2.1 Å resolution. Although it shows most of the canonical features of other SET domains, both the lack of key residues and the presence in the SET-I subdomain of an unusually large loop preclude the interaction of MLL5 SET with its cofactor and substrate. Accordingly, we show that MLL5 is devoid of any in vitro methyltransferase activity on full-length histones and histone H3 peptides. Hence, the three dimensional structure of MLL5 SET domain unveils the structural basis for its lack of methyltransferase activity and suggests a new regulatory mechanism.

Set4 is a chromatin-associated protein, promotes survival during oxidative stress, and regulates stress response genes in yeast

“…8A). Although it remains formally possible that Set4 requires interacting partners or post-translational modifications for its activity or that it targets nonhistone substrates, this finding is consistent with previous reports regarding Set3, UpSET, and MLL5 (15,17,18,23). Additionally, we generated a number of mutations within the SET domain that did not appear to alter Set4 function (Fig.…”

“…Yeast Set3, mammalian MLL5, and the fly protein UpSET contain divergent SET domains that are predicted to lack catalytic activity based on amino acid substitutions in SAM binding sites and the lack of a tyrosine in a stereotypical position important for both SAM and target lysine binding (17,20). Whereas mammalian MLL5 had been postulated to catalyze H3K4 methylation, this activity has not been conclusively demonstrated, and the existence of catalytic activity for MLL5 altogether is unlikely based on biochemical and structural analyses (17,(21)(22)(23). Addition-ally, catalytic activity has not been detected for the fly protein UpSET (18).…”

Common risk variants identified in autism spectrum disorder

“…KMT2E encodes Histone-lysine N-methyltransferase 2E and forms a family together with SETD5 117,118 . Evidence suggest that recognition of the histone H3K4me3 mark by the KMT2E PHD finger can facilitate the recruitment of KMT2E to transcription-active chromatin regions 119,120 .…”

miR-126-5p promotes retinal endothelial cell survival through SetD5 regulatio in neurons

“…However, SetD5 shares higher homologies with mammalian MLL5 (KMT2E), Drosophila UpSET and yeast Set3, three members of this family of proteins that do not show methyltransferase activity (Pijnappel et al, 2001;Rincon-Arano et al, 2012;Sebastian et al, 2009). Therefore, it was recently proposed that MLL5 and SetD5 should be separated from the active methyltransferase family (Mas-Y-Mas et al, 2016). SetD5 functions are not yet known but mutations of its gene are associated with human neurodevelopmental disorders (Grozeva et al, 2014;Kuechler et al, 2015;Parenti et al, 2017;Szczałuba et al, 2016) and prostate cancer (Sowalsky et al, 2015).…”