Deciphering the structure of the condensin protein complex

Krepel, Dana; Cheng, Ryan R.; Pierro, Michele Di; Onuchic, José N.

doi:10.1073/pnas.1812770115

Cited by 19 publications

(17 citation statements)

References 54 publications

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“…DCA gives structural information once we realize that the residue pairs that evolve in a correlated way, as revealed by multiple sequence alignments, are likely to be spatially proximate in at least one structure of the conformational ensemble. DCA has already been used to obtain predictions of bacterial SMC protein structures (19,20), but coevolutionary information about the coiled coils is somewhat sparse. To understand the coiled-coil structural dynamics, we therefore also employed an optimized transferable coarse-grained protein force Significance SMC−kleisin protein complexes play an important role in establishing the 3-dimensional organization of DNA in cells.…”

Section: Dna Topologymentioning

confidence: 99%

Braiding topology and the energy landscape of chromosome organization proteins

Krepel

Davtyan

Schafer

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Assemblies of structural maintenance of chromosomes (SMC) proteins and kleisin subunits are essential to chromosome organization and segregation across all kingdoms of life. While structural data exist for parts of the SMC−kleisin complexes, complete structures of the entire complexes have yet to be determined, making mechanistic studies difficult. Using an integrative approach that combines crystallographic structural information about the globular subdomains, along with coevolutionary information and an energy landscape optimized force field (AWSEM), we predict atomic-scale structures for several tripartite SMC−kleisin complexes, including prokaryotic condensin, eukaryotic cohesin, and eukaryotic condensin. The molecular dynamics simulations of the SMC−kleisin protein complexes suggest that these complexes exist as a broad conformational ensemble that is made up of different topological isomers. The simulations suggest a critical role for the SMC coiled-coil regions, where the coils intertwine with various linking numbers. The twist and writhe of these braided coils are coupled with the motion of the SMC head domains, suggesting that the complexes may function as topological motors. Opening, closing, and translation along the DNA of the SMC−kleisin protein complexes would allow these motors to couple to the topology of DNA when DNA is entwined with the braided coils.

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Section: Dna Topologymentioning

confidence: 99%

Braiding topology and the energy landscape of chromosome organization proteins

Krepel

Davtyan

Schafer

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent single-molecule experiments revealed that the budding yeast condensin is a molecular motor [6] that extrudes a DNA loop [7,8]. However, the detailed molecular mechanism of DNA-loop extrusion by condensin and other members of the SMC protein family remains unclear [8][9][10] and has been an ambitious target of computational modeling studies [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Modeling of DNA binding to the condensin hinge domain using molecular dynamics simulations guided by atomic force microscopy

et al. 2021

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The condensin protein complex compacts chromatin during mitosis using its DNA-loop extrusion activity. Previous studies proposed scrunching and loop-capture models as molecular mechanisms for the loop extrusion process, both of which assume the binding of double-strand (ds) DNA to the hinge domain formed at the interface of the condensin subunits Smc2 and Smc4. However, how the hinge domain contacts dsDNA has remained unknown. Here, we conducted atomic force microscopy imaging of the budding yeast condensin holo-complex and used this data as basis for coarse-grained molecular dynamics simulations to model the hinge structure in a transient open conformation. We then simulated the dsDNA binding to open and closed hinge conformations, predicting that dsDNA binds to the outside surface when closed and to the outside and inside surfaces when open. Our simulations also suggested that the hinge can close around dsDNA bound to the inside surface. Based on these simulation results, we speculate that the conformational change of the hinge domain might be essential for the dsDNA binding regulation and play roles in condensin-mediated DNA-loop extrusion.

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“…DNA looping plays a set of diverse and critical roles. In cells, DNA loops can activate or repress genes in prokaryotes (1)(2)(3)(4), organize and compact the genome in eukaryotes (5)(6)(7)(8)(9), or compact the entire genome in a sequence-independent manner in sperm and bacteria (10)(11)(12)(13). In DNA nanoengineering, synthetic looping proteins have allowed for self assembly of DNA-protein nanostructures (14).…”

Section: Introductionmentioning

confidence: 99%

DNA looping by protamine follows a nonuniform spatial distribution

McMillan

Kuntz

Devenica

et al. 2021

Preprint

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DNA looping plays an important role in cells in both regulating and protecting the genome. Often, studies of looping focus on looping by prokaryotic transcription factors like lac repressor or by structural maintenance of chromosomes (SMC) proteins such as condensin. Here, however, we are interested in a different looping method whereby multivalent cations (charge≥+3), such as protamine proteins, neutralize the DNA, causing it to form loops and toroids. We considered two previously proposed mechanisms for DNA looping by protamine. In the first mechanism, protamine stabilizes spontaneous DNA fluctuations, forming randomly distributed loops along the DNA. In the second mechanism, protamine binds and bends the DNA to form a loop, creating a distribution of loops that is biased by protamine binding. To differentiate between these mechanisms, we imaged both spontaneous and protamine-induced loops on short-length (≤ 1 μm) DNA fragments using atomic force microscopy (AFM). We then compared the spatial distribution of the loops to several model distributions. A random looping model, which describes the mechanism of spontaneous DNA folding, fit the distribution of spontaneous loops, but it did not fit the distribution of protamine-induced loops. Specifically, it overestimated the number of loops that form at the ends of the molecule and failed to predict a peak in the spatial distribution of loops at an intermediate location along the DNA. An electrostatic multibinding model, which was created to mimic the bind-and-bend mechanism of protamine, was a better fit of the distribution of protamine-induced loops. In this model, multiple protamines bind to the DNA electrostatically within a particular region along the DNA to coordinate the formation of a loop. We speculate that these findings will impact our understanding of protamine’s in vivo role for looping DNA into toroids and the mechanism of DNA condensation by multivalent cations more broadly.SIGNIFICANCEDNA looping is important in a variety of both in vivo functions (e.g. gene regulation) and in vitro applications (e.g. DNA origami). Here, we sought a mechanistic understanding of DNA looping by multivalent cations (≥+3), which condense DNA into loops and toroids. One such multivalent cation is the protein protamine, which condenses DNA in sperm. We investigated the mechanism for loop formation by protamine and found that the experimental data was consistent with an electrostatic multibinding model in which two protamines bind electrostatically to the DNA within a 50-nm region to form a loop. This model is likely general to all multivalent cations and may be helpful in applications involving toroid formation or DNA nanoengineering.

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Deciphering the structure of the condensin protein complex

Abstract: Published under the PNAS license.Data deposition: The atomic coordinates of both open and closed condensin protein complex have been deposited in the Model Archive database, https://modelarchive.org/ (Model Archive ID codes ma-abc6s and ma-ac7jp).

Cited by 19 publications

References 54 publications

Braiding topology and the energy landscape of chromosome organization proteins

Braiding topology and the energy landscape of chromosome organization proteins

Modeling of DNA binding to the condensin hinge domain using molecular dynamics simulations guided by atomic force microscopy

DNA looping by protamine follows a nonuniform spatial distribution

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