CHD4 Sandbox: Difference between revisions

The alpha1, aplha2, and alpha3 helices fold and form loops within the histone proteins thus connecting each helix within a histone[2]. The interaction of an alpha1 and alpha2 (L1) and an alpha2 and alpha3 (L2) loops is referred to as an L1L2 motif. While the interaction of the N-terminal ends of an alpha1 helix of the histone is referred to as an alpha1alpha1 motif [2]. These interactions of loops form points of interaction between the minor groove of the DNA and the histone octamer. Histone heterodimer H3-H4 has an L1L2 interaction at SHL ± 0.5, alpha1alpha1 interaction at SHL ± 1.5, and L1L2 interaction at SHL ± 2.5[2]. Histone heterodimer H2A-H2B has an L1L2 interaction at SHL ± 3.5, alpha1alpha1 interaction at SHL ± 4.5, and L1L2 interaction at SHL ± 5.5[2]. The H3 histone protein has an alphaN interaction with DNA at SHL ± 0.5/6.5 [2].

=CHD4 Functions=

CHD4 has a double chromodomain that interacts CHD4 to the backbone of DNA electrostatically at SHL ±1[1].  The double chromodomain also interacts at the H3 histone tail. The PHD zinc finger is located at SHL ± 0.5 at the C-terminus and the H3 histone tail.

CHD4 also has an ATPase motor domain towards the N-terminus which interacts to the nucleosome at SHL ±2[1]. The ATPase has 2 lobes each containing multiple ATPase motifs and binding sites for the minor groove of DNA, specifically Trp1148, Asn1010, and Arg1127 [1]. Trp1148 inserts into the minor groove from motif Va; Asn1010 inserts at SHL ± 2.5 into the minor groove as well as Arg1127 at SHL ± 2[1]. The ATPase domain lobe 2 also interacts at the acidic residues: Asp1080, Glu1083, Asp1084, and Glu1087 forming a pocket for the H4 histone tail Arg17 to insert into [1]. The acetylation of the H4 histone tail Lys16 weakens the acid-base interaction between the ATPase domain and the H4 histone tail[1]. The ATPase domain lobe 2 interacts with H3 histone core residues Gln76 and Arg83 on the alpha helix 1 at ATPase domain lobe 2 residues Asn1004 and Leu1009 [1].

The binding of the CHD4 ATPase motor domain to the DNA at SHL ± 2 – SHL ± 2.5 and the subsequent closing of the conformation due the binding of ATP pre-hydrolysis, causes a twist and bulge in the DNA thus causing a forward untwisting motion of 1bp toward the dyad axis resulting in the movement of the DNA with relation to the nucleosome[1]. The hydrolysis of ATP causes a reset in conformation of the ATPase for the process to start once more[1]. While the motion of a ratchet on a ratchet strap is not an accurate metaphor for how CHD4 moves, the functionality of a ratchet strap is accurate for the function of CHD4[1].

The nucleosome is able to bind twice to CHD4 due to its symmetric duality with each SHL location roughly mirrored over the dyad axis[1]. A second CHD4 interaction with the nucleosome doesn’t change the complex’s stability or the DNA stability at SHL ± 7, the region of entrance and exit[1].