Sister Chromatid Cohesion Establishment Factor ESCO1 Operates by Substrate-Assisted Catalysis.
Sister chromatid cohesion, formed by the cohesin protein complex, is essential for chromosome segregation. In order for cohesion to be established, the cohesin subunit SMC3 needs to be acetylated by a homolog of the ESCO1/Eco1 acetyltransferases, the enzymatic mechanism of which has remained unknown. Here we report the crystal structure of the ESCO1 acetyltransferase domain in complex with acetyl-coenzyme A, and show by SAXS that ESCO1 is a dimer in solution. The structure reveals an active site that lacks a potential catalytic base side chain. However, mutation of glutamate 789, a surface residue that is close to the automodification target lysine 803, strongly reduces autoacetylation of ESCO1. Moreover, budding yeast Smc3 mutated at the conserved residue D114, adjacent to the cohesion-activating acetylation site K112,K113, cannot be acetylated in vivo. This indicates that ESCO1 controls cohesion through substrate-assisted catalysis. Thus, this study discloses a key mechanism for cohesion establishment.
Structural Genomics Consortium and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Ekaterina
E
Kouznetsova
Department of Cellular and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
Takaharu
T
Kanno
Structural Genomics Consortium and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Tobias
T
Karlberg
Structural Genomics Consortium and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Ann-Gerd
AG
Thorsell
Structural Genomics Consortium and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Magdalena
M
Wisniewska
Department of Biomedicine, University of Bergen, 5020 Bergen, Norway; Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
Petri
P
Kursula
Department of Cellular and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
Camilla
C
Sjögren
Structural Genomics Consortium and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: herwig.schuler@ki.se.
Herwig
H
Schüler
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000123:Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C120372:SMC3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; C479413:ESCO1 protein, human