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The four canonical TPR subunits of human APC/C form related homo-dimeric structures and stack in parallel to form a TPR suprahelix

DOI: 10.1016/j.jmb.2013.04.004 DOI Help

Authors: Ziguo Zhang (Institute of Cancer Research) , Leifu Chang (MRC Laboratory of Molecular Biology) , Jing Yang (Institute of Cancer Research) , Nora Cronin (Institute of Cancer Research) , Kiran Kulkarni (Cancer Research UK London Research Institute) , David Barford (Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: April 2013
Diamond Proposal Number(s): 8015

Open Access Open Access

Abstract: The anaphase-promoting complex or cyclosome (APC/C) is a large E3 RING-cullin ubiquitin ligase composed of between 14 and 15 individual proteins. A striking feature of the APC/C is that only four proteins are involved in directly recognizing target proteins and catalyzing the assembly of a polyubiquitin chain. All other subunits, which account for > 80% of the mass of the APC/C, provide scaffolding functions. A major proportion of these scaffolding subunits are structurally related. In metazoans, there are four canonical tetratricopeptide repeat (TPR) proteins that form homo-dimers (Apc3/Cdc27, Apc6/Cdc16, Apc7 and Apc8/Cdc23). Here, we describe the crystal structure of the N-terminal homo-dimerization domain of Schizosaccharomyces pombe Cdc23 (Cdc23Nterm). Cdc23Nterm is composed of seven contiguous TPR motifs that self-associate through a related mechanism to those of Cdc16 and Cdc27. Using the Cdc23Nterm structure, we generated a model of full-length Cdc23. The resultant ā€œVā€-shaped molecule docks into the Cdc23-assigned density of the human APC/C structure determined using negative stain electron microscopy (EM). Based on sequence conservation, we propose that Apc7 forms a homo-dimeric structure equivalent to those of Cdc16, Cdc23 and Cdc27. The model is consistent with the Apc7-assigned density of the human APC/C EM structure. The four canonical homo-dimeric TPR proteins of human APC/C stack in parallel on one side of the complex. Remarkably, the uniform relative packing of neighboring TPR proteins generates a novel left-handed suprahelical TPR assembly. This finding has implications for understanding the assembly of other TPR-containing multimeric complexes.

Journal Keywords: Aanaphase-Promoting Complex; Tetratricopeptide Repeat (Tpr); Cell Cycle; Crystallography; Single-Particle Electron Microscopy

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography

Other Facilities: ID29, ID14-4 at ESRF

Added On: 19/09/2013 19:06

Documents:
1-s2.0-S0022283613002337-main.pdf

Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)