4K6J

Human cohesin inhibitor WapL

Summary for 4K6J

• Entry DOI: 10.2210/pdb4k6j/pdb
• Descriptor: Wings apart-like protein homolog, SULFATE ION, ACETATE ION, ... (4 entities in total)
• Functional Keywords: heat repeats, cohesin regulator, cell adhesion inhibitor, cell cycle, nuclear protein, protein-binding
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Nucleus. Nucleus: Q7Z5K2
• Total number of polymer chains: 2
• Total formula weight: 129321.99

Authors

Tomchick, D.R.,Yu, H.,Ouyang, Z. (deposition date: 2013-04-16, release date: 2013-06-19, Last modification date: 2024-02-28)

Primary citation

Ouyang, Z.,Zheng, G.,Song, J.,Borek, D.M.,Otwinowski, Z.,Brautigam, C.A.,Tomchick, D.R.,Rankin, S.,Yu, H.
Structure of the human cohesin inhibitor Wapl.
Proc.Natl.Acad.Sci.USA, 110:11355-11360, 2013

PubMed Abstract: Cohesin, along with positive regulators, establishes sister-chromatid cohesion by forming a ring to circle chromatin. The wings apart-like protein (Wapl) is a key negative regulator of cohesin and forms a complex with precocious dissociation of sisters protein 5 (Pds5) to promote cohesin release from chromatin. Here we report the crystal structure and functional characterization of human Wapl. Wapl contains a flexible, variable N-terminal region (Wapl-N) and a conserved C-terminal domain (Wapl-C) consisting of eight HEAT (Huntingtin, Elongation factor 3, A subunit, and target of rapamycin) repeats. Wapl-C folds into an elongated structure with two lobes. Structure-based mutagenesis maps the functional surface of Wapl-C to two distinct patches (I and II) on the N lobe and a localized patch (III) on the C lobe. Mutating critical patch I residues weaken Wapl binding to cohesin and diminish sister-chromatid resolution and cohesin release from mitotic chromosomes in human cells and Xenopus egg extracts. Surprisingly, patch III on the C lobe does not contribute to Wapl binding to cohesin or its known regulators. Although patch I mutations reduce Wapl binding to intact cohesin, they do not affect Wapl-Pds5 binding to the cohesin subcomplex of sister chromatid cohesion protein 1 (Scc1) and stromal antigen 2 (SA2) in vitro, which is instead mediated by Wapl-N. Thus, Wapl-N forms extensive interactions with Pds5 and Scc1-SA2. Wapl-C interacts with other cohesin subunits and possibly unknown effectors to trigger cohesin release from chromatin.

PubMed: 23776203
DOI: 10.1073/pnas.1304594110

Experimental method

X-RAY DIFFRACTION (2.6205 Å)