Structural Basis and IP6 Requirement for Pds5-Dependent Cohesin Dynamics

Mol Cell. 2016 Apr 21;62(2):248-259. doi: 10.1016/j.molcel.2016.02.033. Epub 2016 Mar 10.

Abstract

The ring-shaped cohesin complex regulates transcription, DNA repair, and chromosome segregation by dynamically entrapping chromosomes to promote chromosome compaction and sister-chromatid cohesion. The cohesin ring needs to open and close to allow its loading to and release from chromosomes. Cohesin dynamics are controlled by the releasing factors Pds5 and Wapl and the cohesin stabilizer Sororin. Here, we report the crystal structure of human Pds5B bound to a conserved peptide motif found in both Wapl and Sororin. Our structure establishes the basis for how Wapl and Sororin antagonistically influence cohesin dynamics. The structure further reveals that Pds5 can bind inositol hexakisphosphate (IP6). The IP6-binding segment of Pds5B is shaped like the jaw of a plier lever and inhibits the binding of Scc1 to Smc3. We propose that Pds5 stabilizes a transient, open state of cohesin to promote its release from chromosomes.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • Chondroitin Sulfate Proteoglycans / metabolism
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Chromosomes, Human / chemistry
  • Chromosomes, Human / genetics
  • Chromosomes, Human / metabolism*
  • Conserved Sequence
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Kinetics
  • Models, Molecular
  • Nuclear Proteins / metabolism
  • Phosphoproteins / metabolism
  • Phytic Acid / metabolism*
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • Structure-Activity Relationship
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • CDCA5 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PDS5B protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RAD21 protein, human
  • SMC3 protein, human
  • Transcription Factors
  • WAPL protein, human
  • cohesins
  • Phytic Acid