Orchestration of synaptic functions by WAVE regulatory complex-mediated actin reorganization

Abstract

The WAVE regulatory complex (WRC), composed of five components-Cyfip1/Sra1, WAVE/Scar, Abi, Nap1/Nckap1, and Brk1/HSPC300-is essential for proper actin cytoskeletal dynamics and remodeling in eukaryotic cells, likely by matching various patterned signals to Arp2/3-mediated actin nucleation. Accumulating evidence from recent studies has revealed diverse functions of the WRC in neurons, demonstrating its crucial role in dictating the assembly of molecular complexes for the patterning of various trans-synaptic signals. In this review, we discuss recent exciting findings on the physiological role of the WRC in regulating synaptic properties and highlight the involvement of WRC dysfunction in various brain disorders.

Fig. 1. WRC subunit composition and assembly mechanism.

a Schematic depicting WRC subunits and their homologs. The WRC is a five-subunit complex comprising the following protein families: ABI (ABI1, ABI2 or ABI3), WAVE (WAVE1, WAVE2, or WAVE3), Nap1 (Nckap1 or Nckap1L), CYFIP (CYFIP1 or CYFIP2), and HSCP300. aa amino acid, B basic domain, HHR Hox homology region, PP polyproline structure, SH3 Src homology 3 domain, SHD SCAR homology domain, SR serine/threonine-rich region, WAB WAVE-binding domain, WCA WASP homology 2-central-acidic, WHD WAVE homology domain. b Schematic illustration of two modes of WRC activation in actin polymerization. In the absence of Rac1 binding, WRCs exist in an autoinhibited state. Rac1 binding to the A site located at the N-terminus of CYFIP1 induces WRC activation. This destabilizes the meander sequence of WAVE1, which is critical for autoinhibition, inducing a conformal change that triggers the release of the WCA sequence, making it accessible to the ARP2/3 complex. In contrast, Rac1 binding to the D site, located in the C-terminal region of CYFIP1, does not directly activate WRC but does increase the affinity for ARF1 binding between the D site of CYFIP1 and the W helix of the WCA domain of WAVE, allowing the WCA region of WAVE1 to activate ARP2/3.

Fig. 2. Molecular model of WRC recruitment at neuronal synapses.

WRC recruitment is regulated by cell-adhesion proteins and their interacting scaffold proteins at synapses. Various scaffold proteins present in the presynaptic active zone play important roles in WRC recruitment and function. Prominent among them are LAR-RPTPs and Kirrel1. Neurexins (Nrxns) can also bind to the WRC but do not do so directly; instead, they bind indirectly through presynaptic scaffolding proteins, including syntenin, ELKS, liprin-α, PP2A, CASK, Caskins and Nck. In addition to interacting directly with the WRC through their WIRS motif, LAR-RPTPs can also indirectly bind the WRC through interactions with Ena, Abl, and Caskins. Robo receptors, Nlgns, neogenin, Slitrks, and latrophilins are also located at the postsynapse and might recruit the WRC through their WIRS motif.

Fig. 3. Implication of WRC components in various neurological disorders.

Schematic of the neurological disorders discussed in the current paper that are related to dysfunctions of each WRC component. Dysfunction of WAVE1/2, NAP1, ABI3 and CYFIP1/2 might cause neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. ASD autism spectrum disorder, AD Alzheimer’s disease, EIEE early infantile epileptic encephalopathy, ID intellectual disability, PD Parkinson’s disease.