Trends in Biochemical Sciences
ReviewWD40 proteins propel cellular networks
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
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These authors contributed equally.