scholarly journals Hit the brakes – a new perspective on the loop extrusion mechanism of cohesin and other SMC complexes

2021 ◽  
Vol 134 (1) ◽  
pp. jcs247577
Author(s):  
Avi Matityahu ◽  
Itay Onn
Keyword(s):  
Present Model ◽  
Protein Complexes ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Order Structure ◽  
Chromatid Cohesion ◽  
Topologically Associated Domains ◽  
Extrusion Mechanism ◽  
New Perspective ◽  
Structural Maintenance Of Chromosome

ABSTRACTThe three-dimensional structure of chromatin is determined by the action of protein complexes of the structural maintenance of chromosome (SMC) family. Eukaryotic cells contain three SMC complexes, cohesin, condensin, and a complex of Smc5 and Smc6. Initially, cohesin was linked to sister chromatid cohesion, the process that ensures the fidelity of chromosome segregation in mitosis. In recent years, a second function in the organization of interphase chromatin into topologically associated domains has been determined, and loop extrusion has emerged as the leading mechanism of this process. Interestingly, fundamental mechanistic differences exist between mitotic tethering and loop extrusion. As distinct molecular switches that aim to suppress loop extrusion in different biological contexts have been identified, we hypothesize here that loop extrusion is the default biochemical activity of cohesin and that its suppression shifts cohesin into a tethering mode. With this model, we aim to provide an explanation for how loop extrusion and tethering can coexist in a single cohesin complex and also apply it to the other eukaryotic SMC complexes, describing both similarities and differences between them. Finally, we present model-derived molecular predictions that can be tested experimentally, thus offering a new perspective on the mechanisms by which SMC complexes shape the higher-order structure of chromatin.

scholarly journals The origins and evolution of functional modules: lessons from protein complexes

2006 ◽  
Vol 361 (1467) ◽  
pp. 507-517 ◽  
Author(s):  
Jose B Pereira-Leal ◽  
Emmanuel D Levy ◽  
Sarah A Teichmann
Keyword(s):  
Cellular Networks ◽  
Metabolic Networks ◽  
Protein Complexes ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Functional Modules ◽  
Evolutionary Mechanisms ◽  
Loosely Coupled ◽  
Transcriptional Regulatory ◽  
Physical Interactions

Modularity is an attribute of a system that can be decomposed into a set of cohesive entities that are loosely coupled. Many cellular networks can be decomposed into functional modules—each functionally separable from the other modules. The protein complexes in physical protein interaction networks are a good example of this, and here we focus on their origins and evolution. We investigate the emergence of protein complexes and physical interactions between proteins by duplication, and review other mechanisms. We dissect the dataset of protein complexes of known three-dimensional structure, and show that roughly 90% of these complexes contain contacts between identical proteins within the same complex. Proteins that are shared across different complexes occur frequently, and they tend to be essential genes more often than members of a single protein complex. We also provide a perspective on the evolutionary mechanisms driving the growth of other modular cellular networks such as transcriptional regulatory and metabolic networks.

scholarly journals Protein Interaction Z Score Assessment (PIZSA): an empirical scoring scheme for evaluation of protein–protein interactions

2019 ◽  
Vol 47 (W1) ◽  
pp. W331-W337 ◽  
Author(s):  
Ankit A Roy ◽  
Abhilesh S Dhawanjewar ◽  
Parichit Sharma ◽  
Gulzar Singh ◽  
M S Madhusudhan
Keyword(s):  
Protein Interactions ◽  
Protein Complexes ◽  
Three Dimensional ◽  
Optimal Number ◽  
Dimensional Structure ◽  
Side Chain ◽  
Interface Residue ◽  
Z Score ◽  
Protein Protein Interactions ◽  
Residue Contacts

Abstract Our web server, PIZSA (http://cospi.iiserpune.ac.in/pizsa), assesses the likelihood of protein–protein interactions by assigning a Z Score computed from interface residue contacts. Our score takes into account the optimal number of atoms that mediate the interaction between pairs of residues and whether these contacts emanate from the main chain or side chain. We tested the score on 174 native interactions for which 100 decoys each were constructed using ZDOCK. The native structure scored better than any of the decoys in 146 cases and was able to rank within the 95th percentile in 162 cases. This easily outperforms a competing method, CIPS. We also benchmarked our scoring scheme on 15 targets from the CAPRI dataset and found that our method had results comparable to that of CIPS. Further, our method is able to analyse higher order protein complexes without the need to explicitly identify chains as receptors or ligands. The PIZSA server is easy to use and could be used to score any input three-dimensional structure and provide a residue pair-wise break up of the results. Attractively, our server offers a platform for users to upload their own potentials and could serve as an ideal testing ground for this class of scoring schemes.

Low-frequency seismology and the three-dimensional structure of the Earth

1989 ◽  
Vol 328 (1599) ◽  
pp. 329-349 ◽  
Keyword(s):  
Large Scale ◽  
Inner Core ◽  
Three Dimensional ◽  
Low Frequency ◽  
Quantitative Agreement ◽  
Phase Behaviour ◽  
Dimensional Structure ◽  
Order Structure ◽  
Three Dimensional Structure ◽  
The Earth

We attempt to catalogue those features of the three-dimensional structure of the Earth that are well-constrained by low-frequency data (i.e. periods longer than about 125 seconds). The dominant signals in such data are the surface-wave equivalent modes whose phase characteristics are mainly affected by a large scale structure of harmonic degree two in the upper mantle. Available aspherical models predict this phase behaviour quite well, but do not give an accurate prediction of the observed waveforms and we must appeal to higher-order structure an d /o r coupling effects to give the observed complexity of the data. Strong splitting of modes which sample the cores of the Earth is also observed and, though we do not yet have a model of aspherical structure which gives quantitative agreement with these data, anisotropy or large-scale aspherical structure in the inner core appears to be required to model the observed signal.

scholarly journals Smc5/6 Is Required for Repair at Collapsed Replication Forks

2006 ◽  
Vol 26 (24) ◽  
pp. 9387-9401 ◽  
Author(s):  
Eleni Ampatzidou ◽  
Anja Irmisch ◽  
Matthew J. O'Connell ◽  
Johanne M. Murray
Keyword(s):  
Homologous Recombination ◽  
Protein Complexes ◽  
S Phase ◽  
Replication Forks ◽  
Replication Arrest ◽  
Recombination Proteins ◽  
Independent Functions ◽  
Chromatid Cohesion ◽  
Recombination Repair ◽  
Structural Maintenance Of Chromosome

ABSTRACT In eukaryotes, three pairs of structural-maintenance-of-chromosome (SMC) proteins are found in conserved multisubunit protein complexes required for chromosomal organization. Cohesin, the Smc1/3 complex, mediates sister chromatid cohesion while two condensin complexes containing Smc2/4 facilitate chromosome condensation. Smc5/6 scaffolds an essential complex required for homologous recombination repair. We have examined the response of smc6 mutants to the inhibition of DNA replication. We define homologous recombination-dependent and -independent functions for Smc6 during replication inhibition and provide evidence for a Rad60-independent function within S phase, in addition to a Rad60-dependent function following S phase. Both genetic and physical data show that when forks collapse (i.e., are not stabilized by the Cds1Chk2 checkpoint), Smc6 is required for the effective repair of resulting lesions but not for the recruitment of recombination proteins. We further demonstrate that when the Rad60-dependent, post-S-phase Smc6 function is compromised, the resulting recombination-dependent DNA intermediates that accumulate following release from replication arrest are not recognized by the G2/M checkpoint.

scholarly journals Architectural proteins CTCF and cohesin have distinct roles in modulating the higher order structure and expression of the CFTR locus

2014 ◽  
Vol 42 (15) ◽  
pp. 9612-9622 ◽  
Author(s):  
Nehal Gosalia ◽  
Daniel Neems ◽  
Jenny L. Kerschner ◽  
Steven T. Kosak ◽  
Ann Harris
Keyword(s):  
Nuclear Periphery ◽  
Three Dimensional ◽  
Higher Order ◽  
Ctcf Binding ◽  
Cftr Gene ◽  
Dimensional Structure ◽  
Order Structure ◽  
Cis Acting ◽  
Architectural Proteins ◽  
Enhancer Blocking

Abstract Higher order chromatin structures across the genome are maintained in part by the architectural proteins CCCTC binding factor (CTCF) and the cohesin complex, which co-localize at many sites across the genome. Here, we examine the role of these proteins in mediating chromatin structure at the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encompasses nearly 200 kb flanked by CTCF-binding enhancer-blocking insulator elements and is regulated by cell-type-specific intronic enhancers, which loop to the promoter in the active locus. SiRNA-mediated depletion of CTCF or the cohesin component, RAD21, showed that these two factors have distinct roles in regulating the higher order organization of CFTR. CTCF mediates the interactions between CTCF/cohesin binding sites, some of which have enhancer-blocking insulator activity. Cohesin shares this tethering role, but in addition stabilizes interactions between the promoter and cis-acting intronic elements including enhancers, which are also dependent on the forkhead box A1/A2 (FOXA1/A2) transcription factors (TFs). Disruption of the three-dimensional structure of the CFTR gene by depletion of CTCF or RAD21 increases gene expression, which is accompanied by alterations in histone modifications and TF occupancy across the locus, and causes internalization of the gene from the nuclear periphery.

scholarly journals Rings, bracelet or snaps: fashionable alternatives for Smc complexes

2005 ◽  
Vol 360 (1455) ◽  
pp. 537-542 ◽  
Author(s):  
Catherine E Huang ◽  
Mark Milutinovich ◽  
Douglas Koshland
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Protein Complexes ◽  
Coiled Coil ◽  
Structural Features ◽  
Gene Repression ◽  
Chromosome Organization ◽  
Structural Components ◽  
Chromatid Cohesion ◽  
Structural Maintenance Of Chromosome

The mechanism of higher order chromosome organization has eluded researchers for over 100 years. A breakthrough occurred with the discovery of multi-subunit protein complexes that contain a core of two molecules from the structural maintenance of chromosome (Smc) family. Smc complexes are important structural components of chromosome organization in diverse aspects of DNA metabolism, including sister chromatid cohesion, condensation, global gene repression, DNA repair and homologous recombination. In these different processes, Smc complexes may facilitate chromosome organization by tethering together two parts of the same or different chromatin strands. The mechanism of tethering by Smc complexes remains to be elucidated, but a number of intriguing topological alternatives are suggested by the unusual structural features of Smc complexes, including their large coiled-coil domains and ATPase activities. Distinguishing between these possibilities will require innovative new approaches.

scholarly journals Three-dimensional topology of the SMC2/SMC4 subcomplex from chicken condensin I revealed by cross-linking and molecular modelling

Open Biology ◽  
2015 ◽  
Vol 5 (2) ◽  
pp. 150005 ◽  
Author(s):  
Helena Barysz ◽  
Ji Hun Kim ◽  
Zhuo Angel Chen ◽  
Damien F. Hudson ◽  
Juri Rappsilber ◽  
...  
Keyword(s):  
Structure Prediction ◽  
Structural Information ◽  
Protein Complexes ◽  
Three Dimensional ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Dimensional Structure ◽  
Cross Linking ◽  
Mitotic Chromosomes ◽  
Essential Components

SMC proteins are essential components of three protein complexes that are important for chromosome structure and function. The cohesin complex holds replicated sister chromatids together, whereas the condensin complex has an essential role in mitotic chromosome architecture. Both are involved in interphase genome organization. SMC-containing complexes are large (more than 650 kDa for condensin) and contain long anti-parallel coiled-coils. They are thus difficult subjects for conventional crystallographic and electron cryomicroscopic studies. Here, we have used amino acid-selective cross-linking and mass spectrometry combined with structure prediction to develop a full-length molecular draft three-dimensional structure of the SMC2/SMC4 dimeric backbone of chicken condensin. We assembled homology-based molecular models of the globular heads and hinges with the lengthy coiled-coils modelled in fragments, using numerous high-confidence cross-links and accounting for potential irregularities. Our experiments reveal that isolated condensin complexes can exist with their coiled-coil segments closely apposed to one another along their lengths and define the relative spatial alignment of the two anti-parallel coils. The centres of the coiled-coils can also approach one another closely in situ in mitotic chromosomes. In addition to revealing structural information, our cross-linking data suggest that both H2A and H4 may have roles in condensin interactions with chromatin.

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