WASP family proteins: Molecular mechanisms and implications in human disease

Abstract

Proteins of the Wiskott-Aldrich syndrome protein (WASP) family play a central role in regulating actin cytoskeletal dynamics in a wide range of cellular processes. Genetic mutations or misregulation of these proteins are tightly associated with many diseases. The WASP-family proteins act by transmitting various upstream signals to their conserved WH2-Central-Acidic (WCA) peptide sequence at the C-terminus, which in turn binds to the Arp2/3 complex to stimulate the formation of branched actin networks at membranes. Despite this common feature, the regulatory mechanisms and cellular functions of distinct WASP-family proteins are very different. Here, we summarize and clarify our current understanding of WASP-family proteins and how disruption of their functions is related to human disease.

Keywords: Actin; Arp2/3; Cyfip; HEM; JMY; SCAR; SHRC; SWIP; Sra1; Strumpellin; VCA; WASH; WASP; WAVE; WCA; WHAMM; WHIMP; WRC; Wiskott-Aldrich syndrome.

Figure 1.. WASP-family protein domain structure and cellular function.

Schematic showing domain organization of different WASP-family proteins found in mammals (left) and their main functions and localizations in the cell (right). Domain structures are drawn to scale. Based on the structural homology from AlphaFold 2 prediction shown in Figure 5, we re-define WHAMM and JMY N-terminal domain as WJHD (WHAMM and JMY homology domain). WH1: WASP homology 1; GBD: GTPase binding domain; PRR: proline-rich region; WCA: WH2-central-acidic domain; WHD: WAVE homology domain; WAHD: WASH homology domain; LIR: LC3-interacting region; WJHD: WHAMM and JMY homology domain; J-loop: JMY-specific loop; CC: coiled coil domain; NLS: nuclear localization signal; WHDL: WAVE homology domain-like. “++” indicates positively charged sequence.

Figure 2.. WASP and N-WASP.

(A) Major mechanisms underlying WASP and N-WASP auto-inhibition, activation, membrane localization, and oligomerization. (B) Schematic showing how different regulatory ligands interact with WASP and N-WASP. Text boxes show representative ligands in indicated category and diseases caused by or associated with WASP and N-WASP. Hotspots in WASP where most missense mutations in patients are clustered are indicated.

Figure 3.. WAVE regulatory complex (WRC).

(A) Schematic showing mechanisms by which the WRC keeps WAVE auto-inhibited in the basal state, becomes activated by GTPase binding, and translocated to the membrane by directly interacting with membrane proteins and acidic phospholipids. “++++” indicates the positively charged side of the WRC. WAVE for WAVE1/2/3, Abi for Abi1/2/3, Hem for Hem1/Nap2, Cyfip for Sra1/Cyfip2. NBF: Nap1 binding fragment. (B) Schematic showing how different regulatory ligands interact with the WRC. Text boxes show representative ligands in indicated category and diseases caused by or associated with WRC subunits. Hotspots in the WRC where most missense mutations in patients are clustered are indicated. Ligands that bind to individual subunits of the WRC, but do not bind to the fully assembled WRC are not listed, such as N-WASP, FMRP, and eIF4E.

Figure 4.. WASH regulatory complex (SHRC).

(A) Schematic showing mechanisms by which the SHRC may keep WASH auto-inhibited in the basal state and be activated and recruited to the endosomal membrane to regulate retromer- and CCC-retriever-mediated cargo sorting. The relative position of each subunit in the SHRC is based on its homology to the WRC. “++++?” indicates a positively charged surface possibly existing in the SHRC based on its resemblance to the WRC. “GTPase?” indicates the uncertainty of whether and what GTPase directly binds to the SHRC to induce activation. LFa: LF-(D/E)_3–10-LF sequence, which directly binds to VPS35 in retromer. (B) Schematic showing how different regulatory ligands interact with the SHRC. Text boxes show representative ligands in indicated category and diseases caused by or associated with SHRC subunits.

Figure 5.. WHAMM and JMY.

(A-B) Mechanisms underlying WHAMM and JMY membrane localization and inhibition, respectively. Text boxes show known interacting ligands and associated diseases. (C) Overlay of the N-terminal structures of WHAMM and JMY predicted by AlphaFold 2. As the relative orientation between the two domains is different for WHAMM and JMY, shown in the cartoon is the two domains of JMY separately aligned to WHAMM. For clarity, unstructured sequences are removed from the presentation, including the J-loop insertion in the WJHD of JMY. (D) Comparison of WJHD with two representative PX domains, one from SNX25 (sorting nexin 25, PDB: 5WOE) and the other from SNX22 (PDB: 2ETT). The core PX folding is indicated by similar secondary structural elements. Also indicated are the structural inserts protruding from the core, which are unique to the WJHD and not found in PX domains. The J-loop unique to JMY is indicated by a dotted line.