Abstract:ATP-dependent chromatin remodelers are molecular machines that control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the molecular mechanism of active nucleosome sliding by means of molecular dynamics simulations of the Snf2 remodeler translocase in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the translocase overwrites the original nu… Show more
“…While the present experiments cannot reveal the precise location of twist defects, variation in DNA length has been observed in several nucleosome crystal structures at SHL2 as well as SHL5 (refs. 1,65–67 ), and recent molecular simulations have suggested that SHL1 may accommodate an additional bp more easily than neighbouring DNA segments 68,69 . In accordance with the twist diffusion model 70–72 , translocation of DNA initiated at the entry SHL2 would be absorbed at one or more sites, thereby introducing twist defects.Fig.…”
Section: Discussionmentioning
confidence: 99%
“…With this symmetric arrangement, the SHL2 site where one remodeller ATPase is bound corresponds to the exit-side SHL2 of the other remodeller. With SHL1 and SHL2 sites serving as potential reservoirs for twist defects 68,69 , the buffering capability of the nucleosome suggests that the twist defect created by one remodeller during DNA translocation could transiently affect the ATPase binding site of the opposing remodeller. We speculate that twist defects created by one ATPase could therefore interfere with translocation by the other, providing a simple mechanism for coordinating action of remodellers on opposite sides of the nucleosome.…”
ATP-dependent chromatin remodelling enzymes (remodellers) regulate DNA accessibility in eukaryotic genomes. Many remodellers reposition (slide) nucleosomes, however, how DNA is propagated around the histone octamer during this process is unclear. Here we examine the real-time coordination of remodeller-induced DNA movements on both sides of the nucleosome using three-colour single-molecule FRET. During sliding by Chd1 and SNF2h remodellers, DNA is shifted discontinuously, with movement of entry-side DNA preceding that of exit-side DNA. The temporal delay between these movements implies a single rate-limiting step dependent on ATP binding and transient absorption or buffering of at least one base pair. High-resolution cross-linking experiments show that sliding can be achieved by buffering as few as 3 bp between entry and exit sides of the nucleosome. We propose that DNA buffering ensures nucleosome stability during ATP-dependent remodelling, and provides a means for communication between remodellers acting on opposite sides of the nucleosome.
“…While the present experiments cannot reveal the precise location of twist defects, variation in DNA length has been observed in several nucleosome crystal structures at SHL2 as well as SHL5 (refs. 1,65–67 ), and recent molecular simulations have suggested that SHL1 may accommodate an additional bp more easily than neighbouring DNA segments 68,69 . In accordance with the twist diffusion model 70–72 , translocation of DNA initiated at the entry SHL2 would be absorbed at one or more sites, thereby introducing twist defects.Fig.…”
Section: Discussionmentioning
confidence: 99%
“…With this symmetric arrangement, the SHL2 site where one remodeller ATPase is bound corresponds to the exit-side SHL2 of the other remodeller. With SHL1 and SHL2 sites serving as potential reservoirs for twist defects 68,69 , the buffering capability of the nucleosome suggests that the twist defect created by one remodeller during DNA translocation could transiently affect the ATPase binding site of the opposing remodeller. We speculate that twist defects created by one ATPase could therefore interfere with translocation by the other, providing a simple mechanism for coordinating action of remodellers on opposite sides of the nucleosome.…”
ATP-dependent chromatin remodelling enzymes (remodellers) regulate DNA accessibility in eukaryotic genomes. Many remodellers reposition (slide) nucleosomes, however, how DNA is propagated around the histone octamer during this process is unclear. Here we examine the real-time coordination of remodeller-induced DNA movements on both sides of the nucleosome using three-colour single-molecule FRET. During sliding by Chd1 and SNF2h remodellers, DNA is shifted discontinuously, with movement of entry-side DNA preceding that of exit-side DNA. The temporal delay between these movements implies a single rate-limiting step dependent on ATP binding and transient absorption or buffering of at least one base pair. High-resolution cross-linking experiments show that sliding can be achieved by buffering as few as 3 bp between entry and exit sides of the nucleosome. We propose that DNA buffering ensures nucleosome stability during ATP-dependent remodelling, and provides a means for communication between remodellers acting on opposite sides of the nucleosome.
“…It is interesting to discuss an analogy to other molecular motors that are known to use the inchworm motions: Some helicases and ATP-dependent chromatin remodelers are known to use the inchworm motions to proceed along DNA [54][55][56]. The inchworm motions in these mole- We observed the hand-over-hand motions as a sub-dominant pathway.…”
Section: The Observed Primary Inchworm Motion Uses One Atp Per a Dimementioning
Cytoplasmic dynein is a two-headed molecular motor that moves to the minus end of microtubule (MT) using ATP hydrolysis free energy. By employing its two heads (motor domains), cytoplasmic dynein shows various bipedal stepping motions; the inchworm and hand-over-hand motions, as well as non-alternate steps of one head. However, the molecular basis to achieve such diverse stepping manners remains obscure. Here, we propose a kinetic model for bipedal motions of cytoplasmic dynein and performed Gillespie Monte Carlo simulations that reproduces most experimental data obtained to date. The model represents status of each motor domain as five states according to conformations, nucleotide- and MT-binding conditions of the domain. Also, the relative positions of the two domains were approximated by three discrete states. Accompanied by ATP hydrolysis cycles, the model dynein stochastically and processively moved forward in multiple steps via diverse pathways, including inchworm and hand-over-hand motions, same as experimental data. The model reproduced key experimental motility-related parameters including velocity and run-length as functions of ATP concentration and external force. Our model reveals that, in a typical inchworm motion, the leading domain moves via the ATP-dependent power-stroke of the linker coupled with a small change in the stalk angle, whereas the lagging domain moves via diffusion dragged by the leading domain. Moreover, the hand-over-hand motion in the model dynein clearly differs from that of kinesin by the usage of the power-stroke.
“…In vivo there are in addition chromatin remodellers at work that use adenosine triphosphate to move nucleosomes along DNA. New experiments [22][23][24] and simulations [25] suggest that at least some of them induce twist defects in the nucleosome. Chromatin remodellers might help nucleosomes to equilibrate their locations along DNA [26], but they might also perturb the intrinsically preferred positioning of nucleosomes, together with other proteins that compete for DNA target sites [10].…”
About three-quarters of eukaryotic DNA is wrapped into nucleosomes; DNA spools with a protein core. The affinity of a given DNA stretch to be incorporated into a nucleosome is known to depend on the base-pair sequence-dependent geometry and elasticity of the DNA double helix. This causes the rotational and translational positioning of nucleosomes. In this study we ask the question whether the latter can be predicted by a simple coarse-grained DNA model with sequence-dependent elasticity, the rigid base-pair model. Whereas this model is known to be rather robust in predicting rotational nucleosome positioning, we show that the translational positioning is a rather subtle effect that is dominated by the guanine-cytosine content dependence of entropy rather than energy. A correct qualitative prediction within the rigid base-pair framework can only be achieved by assuming that DNA elasticity effectively changes on complexation into the nucleosome complex. With that extra assumption we arrive at a model which gives an excellent quantitative agreement to experimental in vitro nucleosome maps, under the additional assumption that nucleosomes equilibrate their positions only locally.
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