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Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
The ring-shaped cohesin complex topologically entraps chromosomes and regulates chromosome segregation, transcription, and DNA repair. The cohesin core consists of the structural maintenance of chromosomes 1 and 3 (Smc1–Smc3) heterodimeric ATPase, the kleisin subunit sister chromatid cohesion 1 (Scc1) that links the two ATPase heads, and the Scc1-bound adaptor protein Scc3. The sister chromatid cohesion 2 and 4 (Scc2–Scc4) complex loads cohesin onto chromosomes. Mutations of cohesin and its regulators, including Scc2, cause human developmental diseases termed cohesinopathy. Here, we report the crystal structure of Chaetomium thermophilum (Ct) Scc2 and examine its interaction with cohesin. Similar to Scc3 and another Scc1-interacting cohesin regulator, precocious dissociation of sisters 5 (Pds5), Scc2 consists mostly of helical repeats that fold into a hook-shaped structure. Scc2 binds to Scc1 through an N-terminal region of Scc1 that overlaps with its Pds5-binding region. Many cohesinopathy mutations target conserved residues in Scc2 and diminish Ct Scc2 binding to Ct Scc1. Pds5 binding to Scc1 weakens the Scc2–Scc1 interaction. Our study defines a functionally important interaction between the kleisin subunit of cohesin and the hook of Scc2. Through competing with Scc2 for Scc1 binding, Pds5 might contribute to the release of Scc2 from loaded cohesin, freeing Scc2 for additional rounds of loading.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Cancer Prevention and Research Inst. of Texas; National Inst. of Health; USDOE; Welch Foundation
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1333417
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 44 Vol. 113; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (63)

NIPBL expression levels in CdLS probands as a predictor of mutation type and phenotypic severity: NIPBL Expression Levels in CdLS Probands as a journal April 2016
Mutation Spectrum and Genotype-Phenotype Correlation in Cornelia de Lange Syndrome journal September 2013
NMRPipe: A multidimensional spectral processing system based on UNIX pipes journal November 1995
Regulation of sister chromatid cohesion during the mitotic cell cycle journal October 2015
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Eco1 Is a Novel Acetyltransferase that Can Acetylate Proteins Involved in Cohesion journal February 2002
Cohesin's Binding to Chromosomes Depends on a Separate Complex Consisting of Scc2 and Scc4 Proteins journal February 2000
Evidence that Loading of Cohesin Onto Chromosomes Involves Opening of Its SMC Hinge journal November 2006
Sororin Mediates Sister Chromatid Cohesion by Antagonizing Wapl journal November 2010
Cohesin’s DNA Exit Gate Is Distinct from Its Entrance Gate and Is Regulated by Acetylation journal August 2012
CTCF and Cohesin: Linking Gene Regulatory Elements with Their Targets journal March 2013
DNA Entry into and Exit out of the Cohesin Ring by an Interlocking Gate Mechanism journal December 2015
Structural Studies Reveal the Functional Modularity of the Scc2-Scc4 Cohesin Loader journal August 2015
Structure of the Pds5-Scc1 Complex and Implications for Cohesin Function journal March 2016
Crystal Structure of the Cohesin Gatekeeper Pds5 and in Complex with Kleisin Scc1 journal March 2016
ATP Hydrolysis Is Required for Cohesin's Association with Chromosomes journal November 2003
Cohesin’s ATPase Activity Couples Cohesin Loading onto DNA with Smc3 Acetylation journal October 2014
Cohesin and Its Regulation: On the Logic of X-Shaped Chromosomes journal October 2014
Structure and function of cohesin's Scc3/SA regulatory subunit journal August 2014
Acetylation of Smc3 by Eco1 Is Required for S Phase Sister Chromatid Cohesion in Both Human and Yeast journal July 2008
An Smc3 Acetylation Cycle Is Essential for Establishment of Sister Chromatid Cohesion journal September 2010
Cohesin Releases DNA through Asymmetric ATPase-Driven Ring Opening journal February 2016
Releasing Activity Disengages Cohesin’s Smc3/Scc1 Interface in a Process Blocked by Acetylation journal February 2016
Magic Acts with the Cohesin Ring journal February 2016
Structural Basis and IP6 Requirement for Pds5-Dependent Cohesin Dynamics journal April 2016
SEDPHAT – A platform for global ITC analysis and global multi-method analysis of molecular interactions journal April 2015
High-Precision Isothermal Titration Calorimetry with Automated Peak-Shape Analysis journal June 2012
The cohesin ring concatenates sister DNA molecules journal July 2008
Mediator and cohesin connect gene expression and chromatin architecture journal August 2010
HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle journal August 2012
Biochemical reconstitution of topological DNA binding by the cohesin ring journal December 2013
NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome journal May 2004
Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B journal May 2004
At the heart of the chromosome: SMC proteins in action journal May 2006
Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion journal August 2014
Pds5 promotes and protects cohesin acetylation journal July 2013
Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells journal August 2015
Cohesinopathies, gene expression, and chromatin organization journal April 2010
The cohesin complex and its roles in chromosome biology journal November 2008
Sister acts: coordinating DNA replication and cohesion establishment journal December 2010
Multiparametric scaling of diffraction intensities journal April 2003
A short history of SHELX journal December 2007
Measurement errors and their consequences in protein crystallography journal October 2003
HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes journal July 2006
The Buccaneer software for automated model building. 1. Tracing protein chains journal August 2006
Recent developments in classical density modification journal March 2010
Diffraction data analysis in the presence of radiation damage journal March 2010
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
Molecular replacement with MOLREP journal December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Identification of patterns in diffraction intensities affected by radiation exposure journal December 2012
Eco1-Dependent Cohesin Acetylation During Establishment of Sister Chromatid Cohesion journal July 2008
A Molecular Determinant for the Establishment of Sister Chromatid Cohesion journal July 2008
Characterization of a DNA exit gate in the human cohesin ring journal November 2014
Closing the cohesin ring: Structure and function of its Smc3-kleisin interface journal November 2014
Cohesin: Its Roles and Mechanisms journal December 2009
Sister Chromatid Cohesion: A Simple Concept with a Complex Reality journal November 2008
The Smc complexes in DNA damage response journal January 2012
Cohesin in development and disease journal August 2013
Structural evidence for Scc4-dependent localization of cohesin loading journal June 2015
The ATPases of cohesin interface with regulators to modulate cohesin-mediated DNA tethering journal November 2015

Cited By (22)

Structural Basis for a Safety-Belt Mechanism That Anchors Condensin to Chromosomes journal October 2017
MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome journal May 2020
A Role for Chromatin Remodeling in Cohesin Loading onto Chromosomes journal May 2019
Structural Basis of an Asymmetric Condensin ATPase Cycle journal June 2019
Structure of the cohesin loader Scc2 journal January 2017
Scc2/Nipbl hops between chromosomal cohesin rings after loading posted_content May 2017
Structural basis of HEAT ‐kleisin interactions in the human condensin I subcomplex journal March 2019
Topological in vitro loading of the budding yeast cohesin ring onto DNA journal October 2018
Towards a Structural Mechanism for Sister Chromatid Cohesion Establishment at the Eukaryotic Replication Fork journal May 2021
Replisome‐Cohesin Interfacing: A Molecular Perspective journal August 2018
New insights into cohesin loading journal June 2017
A tethered-inchworm model of SMC DNA translocation journal September 2018
Suppressor mutation analysis combined with 3D modeling explains cohesin’s capacity to hold and release DNA journal May 2018
Brca2, Pds5 and Wapl differentially control cohesin chromosome association and function posted_content November 2017
Structural basis of HEAT-kleisin interactions in the human condensin I subcomplex posted_content October 2018
The cohesin loader NIPBL interacts with pre-ribosomal RNA and treacle to regulate ribosomal RNA synthesis posted_content June 2019
DNA loop extrusion by human cohesin journal November 2019
Brca2, Pds5 and Wapl differentially control cohesin chromosome association and function journal February 2018
Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins journal October 2017
Isolation of Fission Yeast Condensin Temperature-Sensitive Mutants with Single Amino Acid Substitutions Targeted to Hinge Domain journal March 2019
The CDK Pef1 and protein phosphatase 4 oppose each other for regulating cohesin binding to fission yeast chromosomes journal January 2020
MCM2–7-dependent cohesin loading during S phase promotes sister-chromatid cohesion journal April 2018

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