Molecular Mimicry and Ligand Recognition in Binding and Catalysis by the Histone Demethylase LSD1-CoREST Complex

Abstract

SUMMARY Histone demethylases LSD1 and LSD2 (KDM1A/B) catalyze the oxidative demethylation of Lys4 of histone H3. We employed molecular dynamics simulations to probe the diffusion of the oxygen substrate. Oxygen can reach the catalytic centre independently from the presence of a bound histone peptide, implying that LSD1 can complete subsequent demethylation cycles without detaching from the nucleosomal particle. The simulations highlight the role of a strictly conserved active-site Lys residue providing general insight into the enzymatic mechanism of oxygen-reacting flavoenzymes. The crystal structure of LSD1-CoREST bound to a peptide of the transcription factor SNAIL1 unravels a fascinating example of molecular mimicry. The SNAIL1 N-terminal residues bind to the enzyme active-site cleft, effectively mimicking the H3 tail. This finding predicts that other members of the SNAIL/Scratch transcription factor family might associate to LSD1/2. The combination of selective histone-modifying activity with the distinct recognition mechanisms underlies the biological complexity of LSD1/2.

LSD1/CoREST is an allosteric nanoscale clamp regulated by H3-histone-tail molecular recognition

“…This point is extremely relevant not only in the context of H3 histone molecular recognition. LSD1 could recruit a variety of transcription factors using molecular mimicry mechanisms similar to that proposed for SNAIL1 using the H3-pocket as an anchoring site for their N-terminal tails (22,30). Our MD simulations supply new insight on the gating role of the Lys triad in substrate recognition.…”

“…This nanoscale clamp motion makes LSD1/CoREST particularly suited for binding chromatin and protein partners with varying structural and dynamic complexity. Combined with the H3 histone/SNAIL1 molecular mimicry mechanism supports our working hypothesis that LSD1/CoREST could act as a multi-docking site to competitively anchor an array of structurally and functionally diverse transcription factors that share high N terminus sequence similarity (22,29,30). Here, we investigate the changes of LSD1/ CoREST dynamics occurring upon binding the H3 N-terminal peptide addressing three key questions.…”

“…6B). The role of this region has been neglected thus far, as all X-ray structures deposited to date display the Lys triad as fully open, toward the protein surface (21)(22)(23)(24)(25). An important point that remains to be addressed in the context of LSD1/ CoREST substrate recognition is how substrates with a net positive charge could be favorably attracted toward a binding pocket gated by Lys residues that carry a same, repelling positive charge.…”

“…LSD1/CoREST structural biology architecture is summarized in Fig. 1 on the basis of various studies (21)(22)(23)(24)(25)(26). Recent X-ray crystallography experiments showed that-in addition to host the H3 N-terminal peptide-LSD1/CoREST can bind, as well, to the N-terminal peptide of the transcription factor SNAIL1 through a molecular mimicry mechanism (22).…”

“…1 on the basis of various studies (21)(22)(23)(24)(25)(26). Recent X-ray crystallography experiments showed that-in addition to host the H3 N-terminal peptide-LSD1/CoREST can bind, as well, to the N-terminal peptide of the transcription factor SNAIL1 through a molecular mimicry mechanism (22). This observation has outstanding relevance, because SNAIL1 is a master regulator of the epithelialmesenchymal transition underlying morphogenetic events, such as the establishment of tumor invasiveness (27).…”