The Human Mixed Lineage Leukemia 5 (MLL5), a Sequentially and Structurally Divergent SET Domain-Containing Protein...

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Mixed Lineage Leukemia 5 (MLL5) is crucial for cell development and cycle regulation.
• MLL5 possesses a SET domain, typically associated with histone methyltransferase activity.
• Its PHD domain facilitates chromatin binding via histone H3 interaction.

Purpose of the Study:

• To determine the crystal structure of the unliganded human MLL5 SET domain.
• To elucidate the structural basis for MLL5's potential enzymatic activity.
• To investigate the functional implications of MLL5's structural features.

Main Methods:

• X-ray crystallography was used to obtain the structure of the MLL5 SET domain at 2.1 Å resolution.
• Biochemical assays were performed to test methyltransferase activity on histones and peptides.
• Structural analysis focused on identifying key residues and structural motifs within the SET domain.

Main Results:

• The crystal structure of the MLL5 SET domain was determined.
• Key residues essential for methyltransferase activity were found to be absent.
• An unusually large loop in the SET-I subdomain prevents cofactor and substrate interaction.
• MLL5 demonstrated no detectable in vitro methyltransferase activity.

Conclusions:

• The MLL5 SET domain's structure explains its lack of methyltransferase activity.
• MLL5 may function through mechanisms other than histone methylation.
• The findings suggest a novel regulatory role for MLL5 in cellular processes.