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Structural basis for the recognition of Set1 family Win motifs by WDR5
Author(s) -
Dharmarajan Venkatasubramanian,
Patel Anamika,
Vought Valarie E,
Cosgrove Michael S
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.460.1
Subject(s) - peptide , motif (music) , affinities , plasma protein binding , biology , chemistry , biochemistry , acoustics , physics
The Mixed Lineage Leukemia protein‐1 (MLL1) associates with WDR5, RbBP5 and Ash2L to form the MLL1 core complex that catalyzes mono‐ and dimethylation of histone H3 Lysine 4 (H3K4). We have recently established that WDR5 interacts with MLL1 through a highly conserved W DR5 in teraction ( Win ) motif in MLL1 and a peptide derived from the Win motif in MLL1 has been shown to disrupt this interaction and specifically inhibit the H3K4 dimethylation activity of the MLL1 core complex. The Win motif is highly conserved among the metazoan Set1 family members, however, little is known about how the different Set1 family Win motifs are recognized by WDR5. To understand the molecular details of these interactions, here we compare 3‐dimensional structures and thermodynamic binding properties of different human Set1 family Win motif based peptides bound to WDR5. We show that Win motif peptides derived from human Set1 family members (MLL2, MLL3, MLL4, SET1a and SET1b) interact with WDR5 with dissociation constants (Kd) ranging from 50–470 nM. These binding affinities are 4 to 30‐fold tighter than the interaction between MLL1 Win motif and WDR5. The crystal structure of WDR5 bound to the human SET1a Win motif peptide reveals more favorable interactions outside the Arginine binding pocket in WDR5 that contributes to the increased affinity as compared to that of MLL1 Win motif peptide. We also demonstrate that the human SET1a Win motif peptide is a four‐fold better inhibitor of the H3K4 dimethylation activity of the MLL1 core complex with an IC 50 value of 70 μM. These studies establish the structural basis for the differential interaction affinities between WDR5 and Set1 family Win motifs and suggest a framework for the design of Win motif based peptide inhibitors of Set1 family complexes.