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

Abstract

The complex of lysine-specific demethylase-1 (LSD1/KDM1A) with its corepressor protein CoREST is an exceptionally relevant target for epigenetic drugs. Here, we provide insight into the local and global changes of LSD1/CoREST conformational dynamics that occur upon H3 binding on the basis of a total cumulative time of one microsecond molecular dynamics simulation. The LSD1/CoREST complex functions as an allosteric nanoscale-binding clamp, which is regulated by substrate binding. In the unbound state, LSD1/CoR-EST reversibly visits clamp states that are more open or significantly more closed compared with the available X-ray crystal structures. The Lys triad of residues Lys355, Lys357, and Lys359 gates the entrance of the H3 pocket. H3 binding shifts the pocket breathing dynamics toward open, higher-volume states while reducing the overall flexibility of the LSD1/CoREST nanoscale clamp. We show that the H3 pocket is an allosteric site for the regulation of the rotation of the amino oxidase domain with respect to the Tower domain. The allosteric mechanism relies on the specific reduction of nanoscale domain rotation upon local H3-tail binding. Instead, clamp opening/closing motions that do not involve domain rotation only reduce in amplitude yet are dominant in the bound state. Overall, our data suggest that the H3 binding pocket is a central target site to (i) switch off LSD1 amino oxidase activity, thus H3-tail demethylation; (ii) block the competitive binding of transcription factors; and (iii) prevent chromatin anchoring to LSD1/CoREST. This study underscores the importance of receptor flexibility for future epigenetic drug discovery.chromatin remodeling | epigenetics | protein dynamics | computer simulation | pharmacology E pigenetic drugs have promising, potential advantages compared with other cancer treatments (e.g., radiotherapy or DNA-modifying drugs), because they could act on replication and gene expression by modulating DNA access without altering the sequence and structure of DNA itself. Therefore, epigenetic pharmacology holds great promise to reduce the side effects that typically limit chemotherapy and antineoplastic efficacy. For example, this general, transferable concept is at the basis of the histone deacetylase inhibitors recently introduced for treatment of certain types of lymphomas (1, 2). Lysine-specific demethylase-1 (LSD1 or KDM1A) is overexpressed in many solid tumors such as breast, colon, neuroblastoma, bladder, small cell lung, blood, and prostate cancers (3-11) and plays an important role in leukemia (12), attracting steadily increasing attention as a major target for epigenetic drug discovery (13,14).LSD1 associated to its corepressor protein CoREST catalyzes the oxidative, specific demethylation of the H3 histone N-terminal (H3) mono-and di-methylated Lys4 residue, using flavin adenosine dinucleotide (FAD) as a cofactor (15-21). LSD1/CoREST structural biology architecture is summarized in Fig. 1 on the basis of various studies (21-26). Recent X-ray crystallography experiments sho...

Kink turn sRNA folding upon L7Ae binding using molecular dynamics simulations

“…Previous MD simulations have confirmed this flexibility. 43 In our study, principal component analysis (PCA) [63][64][65][66] was employed to discover the principal movements of these two stems. The ptraj module of AMBER11 was used to solve eigenvalues and corresponding eigenvectors from a covariance matrix and to calculate the contribution of each principal component.…”

G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme

“…LSD1 is associated with CoREST and together they act as an allosteric clamp on nucleosomes to catalyze specific histone H3K4/K9 demethylation (Shi et al 2004;Chen et al 2006;Stavropoulos et al 2006;Yang et al 2006;Forneris et al 2007;Baron and Vellore 2012). Motions of the SWIRM domain and rotation of the AOD of LSD1 must occur when the substrate enters the active site pocket (Baron and Vellore 2012) and it has been demonstrated that both substrate binding and protein-protein interactions modulate LSD1 conformational dynamics and activity (Shi et al 2005;Forneris et al 2007).…”

“…Motions of the SWIRM domain and rotation of the AOD of LSD1 must occur when the substrate enters the active site pocket (Baron and Vellore 2012) and it has been demonstrated that both substrate binding and protein-protein interactions modulate LSD1 conformational dynamics and activity (Shi et al 2005;Forneris et al 2007).…”

Chromatin regulation: How complex does it get?

“…78,79 Structural studies have provided insight into how some of the CoREST complex subunits interact with each other and their chromatin substrate. [80][81][82][83] Importantly, the LSD1 enzyme alone demethylates H3K4 within peptides or bulk histones in vitro. However, only LSD1 in complex with CoREST is capable of catalyzing H3K4 demethylation within nucleosomes.…”