# Disentanglement of the MLL-WDR5 Protein-Protein Recognition Events

> **NIH NIH R01** · SYRACUSE UNIVERSITY · 2020 · $311,200

## Abstract

Project summary
Mixed lineage leukemia protein-1 (MLL1) is a member of the human SET1 family of histone H3 lysine 4
(H3K4) methyltransferases, which include MLL1-4 and SETd1A/B. Rearrangements of MLL1 are
frequently present in acute leukemia, whereas genetic alterations in other SET1 family members are
associated with developmental disorders as well as a number of cancers. A minimal evolutionarily
conserved complex, which is formed by MLL1 and four additional proteins, is required for the sequential
mono- and dimethylation of H3K4. WD40 repeat protein-5 (WDR5), one of the MLL1 core complex
proteins, specifically interacts with a conserved WDR5 interaction motif of the SET1 proteins, also named
the Win motif. Targeting the Win motif-WDR5 interaction with small-molecule drugs and Win-based
peptidomimetics has emerged as a strategic approach for treatment of acute leukemia that harbors the
MLL1 protein, because the MLL1-WDR5 interaction is a key regulatory mechanism of the MLL1
enzymatic activity. However, progress in identifying inhibitors of the MLL1-WDR5 interactions remains
modest due to: (i) the lack of proteomics technologies for the quantitative evaluation of the transient
protein-protein interactions (PPI) at the MLL1-WDR5 interface; (ii) the lack of a mechanistic knowledge
pertaining to the MLL1-WDR5 recognition system. To address these scientific and technological gaps, we
will develop monomeric protein-pore based sensors for sampling transient PPI at single-recognition event
resolution. The central player of these sensors will be the t-FhuA protein pore, a heavily truncated
derivative of ferric hydroxamate uptake component A (FhuA) of E. coli. t-FhuA will be fused to a water-
soluble MLL1 SET binding domain via a short peptide tether. Such a MLL1 binding polypeptide-containing
t-FhuA-based sensor will rely on precise protein engineering, along with biomolecular recognition,
scalable high-resolution electrical recordings, and single-protein channel reconstitution. The presence of
WDR5 will produce a specific, sensitive, and quantitative readout that encompasses reversible current
blockades, the nature of which depends on the PPI strength and WDR5 concentration. The expected
immediate outcomes will be the following: (i) the design, creation, and optimization of the next-generation
t-FhuA-based sensors equipped with single receptor elements for the real-time, selective sampling of
transient PPI in aqueous phase; (ii) the development of a mechanistic and quantitative information on the
Win motif-WDR5 interactions for each SET1 family member; (iii) the multiplexed screening of Win motif-
based inhibitors with improved translational potential. These research studies will ultimately lead to a
fundamental basis for accelerated discoveries in clinical molecular diagnostics, proteomics, and biosensor
technology.

## Key facts

- **NIH application ID:** 9938637
- **Project number:** 5R01GM129429-03
- **Recipient organization:** SYRACUSE UNIVERSITY
- **Principal Investigator:** LIVIU MOVILEANU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $311,200
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938637

## Citation

> US National Institutes of Health, RePORTER application 9938637, Disentanglement of the MLL-WDR5 Protein-Protein Recognition Events (5R01GM129429-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938637. Licensed CC0.

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