Review
WD40 proteins propel cellular networks

https://doi.org/10.1016/j.tibs.2010.04.003Get rights and content

Recent findings indicate that WD40 domains play central roles in biological processes by acting as hubs in cellular networks; however, they have been studied less intensely than other common domains, such as the kinase, PDZ or SH3 domains. As suggested by various interactome studies, they are among the most promiscuous interactors. Structural studies suggest that this property stems from their ability, as scaffolds, to interact with diverse proteins, peptides or nucleic acids using multiple surfaces or modes of interaction. A general scaffolding role is supported by the fact that no WD40 domain has been found with intrinsic enzymatic activity despite often being part of large molecular machines. We discuss the WD40 domain distributions in protein networks and structures of WD40-containing assemblies to demonstrate their versatility in mediating critical cellular functions.

Section snippets

WD40 domains perform diverse cellular functions

Regulatory interactions in living systems are not controlled by stochastic processes such as diffusion, but rather by strict spatio-temporal instructions, for example by cooperative formation of large and dynamic multi-protein complexes through the help of scaffolding proteins 1, 2. WD40 (also called WD-repeat) domains are prominent features within proteins that mediate diverse protein–protein interactions, including those involved in scaffolding and the cooperative assembly and regulation of

WD40 domains are abundant in eukaryotic proteomes

WD40 domains are among the ten most abundant domain types across eukaryotic proteomes (Figure 2). Other abundant domain types are involved in transcription (e.g. zinc fingers), post transcriptional control (RNA recognition motif domain (or RRM) domains), ubiquitylation (RING-finger domains), cell–cell communication and the immune system (immunoglobulin domains) and are not normally involved in signalling pathways, whereas more typical signalling domains (e.g. SH3, PDZ and SH2 domains) appear to

WD40: the cell's most pervasive interactor?

WD40 propellers are large domains of ∼300 amino acids and can be considered to have three distinct surfaces available for interactions: the top region of the propeller, which is defined as the part of the structure where the loops connecting D and A strands of the WD-repeats lie; the bottom region; and the circumference (Figure 1).

Interestingly, most protein–protein and protein–peptide interactions involve the entry site to the central channel of the β-propeller (Figure 3a and Box 1),

Why WD40 domains?

Why does nature exploit the WD40 domain seemingly more often than other possible domain candidates? There are several possible explanations. As mentioned above, the simplest hypothesis is that the structure lends itself well to binding many proteins by having many suitable surfaces. This is an appealing notion, but one that would clearly be true also for many other domains of a similar size found in nature.

Another structurally compelling reason is that WD40 domains form highly symmetrical

Concluding remarks

Scaffolds, by definition, facilitate the function and activity of other proteins and, as such, they usually are the last object to be uncovered as researchers tend to study the outcome of the scaffolding function rather than the scaffold itself. Just as one tends to marvel at the elegance of an arch in a building rather than thinking about how it was constructed, scientists often focus on the business end of a complex (e.g. kinase activity) before worrying about how it comes to be active or

Acknowledgements

We thank Toby Gibson, Sebastian Glatt and Matthew Betts for critical reading of the manuscript and Robert Weatheritt for help with the peptide motifs of the WD40 interactors. This work was in part supported by the European Commission under FP6, contract LSHG-CT-2005-512028. C.U.S. gratefully acknowledges financial support by the Marie Curie framework program 7.

Glossary

CLH
clathrin heavy chain repeat homology domains represent a repeat found at the C-terminus of clathrin heavy chains as well as in vacuolar protein sorting-associated (VPS) proteins.
FBOX
FBOX domains were first identified in cyclin F and act as receptors for ubiquitylation targets. Several FBOX domains are coupled to leucine-rich or WD40 domains.
FYVE
special type of zinc finger domain named after the first letter of four domain-containing proteins: Fab1, YOTB/ZK632.12, Vac1 and EEA1. FYVE domains

References (69)

  • G. Wu

    Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase

    Mol. Cell

    (2003)
  • S. Orlicky

    Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase

    Cell

    (2003)
  • D.K. Wilson

    The 1.1-angstrom structure of the spindle checkpoint protein Bub3p reveals functional regions

    J. Biol. Chem.

    (2005)
  • R. Gaudet

    Crystal structure at 2.4 angstroms resolution of the complex of transducin betagamma and its regulator, phosducin

    Cell

    (1996)
  • Z. Han

    Structural basis of EZH2 recognition by EED

    Structure

    (2007)
  • N.V. Murzina

    Structural basis for the recognition of histone H4 by the histone-chaperone RbAp46

    Structure

    (2008)
  • D.M. Virshup

    Protein phosphatase 2A: a panoply of enzymes

    Curr. Opin. Cell Biol.

    (2000)
  • Y. Xu

    Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation

    Mol. Cell

    (2008)
  • Y. Xu

    Structure of the protein phosphatase 2A holoenzyme

    Cell

    (2006)
  • C.S. Moreno

    WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A

    J. Biol. Chem.

    (2000)
  • K.C. Hsia

    Architecture of a coat for the nuclear pore membrane

    Cell

    (2007)
  • A. Scrima

    Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex

    Cell

    (2008)
  • S. Jackson et al.

    CRL4s: the CUL4-RING E3 ubiquitin ligases

    Trends Biochem. Sci.

    (2009)
  • G.M. Salem

    Correlation of observed fold frequency with the occurrence of local structural motifs

    J. Mol. Biol.

    (1999)
  • I. Garcia-Higuera

    Folding a WD repeat propeller. Role of highly conserved aspartic acid residues in the G protein beta subunit and Sec13

    J. Biol. Chem.

    (1998)
  • P. Aloy

    The relationship between sequence and interaction divergence in proteins

    J. Mol. Biol.

    (2003)
  • A.G. Murzin

    SCOP: a structural classification of proteins database for the investigation of sequences and structures

    J. Mol. Biol.

    (1995)
  • E. Krissinel et al.

    Inference of macromolecular assemblies from crystalline state

    J. Mol. Biol.

    (2007)
  • B.H. Jennings

    Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor

    Mol. Cell

    (2006)
  • C.A. Johnston

    Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2

    Structure

    (2008)
  • J.J. Song et al.

    WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket

    J. Biol. Chem.

    (2008)
  • K. Yonezawa

    Raptor, a binding partner of target of rapamycin

    Biochem. Biophys. Res. Commun.

    (2004)
  • S. Mukai et al.

    Molecular mechanisms of import of peroxisome-targeting signal type 2 (PTS2) proteins by PTS2 receptor Pex7p and PTS1 receptor Pex5pL

    J. Biol. Chem.

    (2006)
  • S. Hurtley

    Spatial cell biology. Location, location, location

    Science

    (2009)
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