Abstract
SummaryThe condensin protein complex plays a key role in the structural organization of genomes. How the ATPase activity of its SMC subunits drives large-scale changes in chromosome topology has remained unknown. Here we reconstruct, at near-atomic resolution, the sequence of events that take place during the condensin ATPase cycle. We show that ATP binding induces a conformational switch in the Smc4 head domain that releases its hitherto undescribed interaction with the Ycs4 HEAT-repeat subunit and promotes its engagement with the Smc2 head into an asymmetric heterodimer. SMC head dimerization subsequently enables nucleotide binding at the second active site and disengages the Brn1 kleisin subunit from the Smc2 coiled coil to open the condensin ring. These large-scale transitions in the condensin architecture lay out a mechanistic path for its ability to extrude DNA helices into large loop structures.
Highlights
Multi-subunit protein complexes of the structural maintenance of chromosomes (SMC) family direct large-scale organizational changes in genome architecture that are essential for all aspects of chromosome biology
Structural Basis for Asymmetric ATP Binding by the Condensin SMC Head Domains To gain functional insights into the condensin ATPase cycle, we solved the crystal structures of Smc2hd and the Smc4hd-Brn1C complex of the thermophilic yeast Chaetomium thermophilum (Ct; Figure S1A; Table S1) to 2.6- or 3.0-Aresolution, respectively (Figure 1A; Table 1)
The Ct Smc4hd crystal structure displayed distinct density for the C-terminal Brn1 region, which folds into a winged helix domain (wHD) and binds to the cap’ face of the SMC ATPase
Summary
Multi-subunit protein complexes of the structural maintenance of chromosomes (SMC) family direct large-scale organizational changes in genome architecture that are essential for all aspects of chromosome biology. How the energy of nucleotide binding, hydrolysis, and release is converted into DNA translocation and looping movements has remained unknown, but currently available models rely on mechanochemical coupling of the ATPase cycle to large conformational transitions that affect chromosome interactions by creating topological compartments or contact sites that entrap or directly bind DNA, respectively (Gruber, 2017; Hassler et al, 2018) Based on their homology to ATP binding cassette (ABC) transmembrane transporters and the Rad DNA damage repair protein (Hopfner, 2016), the two globular ATPase ‘‘head’’ domains situated at the ends of 50-nm-long intra-molecular coiled coils of a heterodimer of condensin’s Smc and Smc subunits are thought to sandwich a pair of ATP molecules between composite catalytic sites, each composed of Walker A (P loop) and Walker B motifs of one head and a so-called ABC signature motif of the opposite head.
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