STRC Research

WH2 Domain Actin-Binding Structures — Chéreau et al. 2005

2 min read

WH2 Domain Actin-Binding Structures — Chéreau et al. 2005

Citation: Chéreau, D. et al. (2005). Actin-bound structures of Wiskott–Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly. PNAS, 102(46), 16644-16649. DOI: 10.1073/pnas.0506024102

Authors: Boston Biomedical Research Institute, Dominguez lab.

Key Claims

  1. WH2 is an ~20 aa actin-binding motif. Crystal structures of WH2–actin determined for WASP, WAVE2, and WIP — all bind in the cleft between actin subdomains 1 and 3.
  2. WH2 binds actin with ~10-fold higher affinity than thymosin-β (Tβ), despite having a smaller binding interface. The N-terminal amphiphilic α-helix accounts for most of this affinity.
  3. Two types of WH2: short (~17 aa, WASP/WAVE) and long (~27 aa, WIP/MIM). Long WH2 penetrates deeper into the nucleotide cleft.
  4. WH2 lacks the C-terminal α-helix that makes Tβ a monomer-sequestering domain. This is key: WH2 can coexist with F-actin intersubunit contacts, allowing tandem WH2 domains to line up actin monomers for filament nucleation.
  5. Nucleotide exchange inhibition is a function of the N-terminal α-helix binding between subdomains 1 and 3 — not the C-terminal extension.
  6. Tandem short WH2 domains connected by short linkers = filament nucleation template. This is how spire (4× WH2) works.
  7. WH2 binds ATP-actin with higher affinity than ADP-actin — relevant for processive elongation models.

Structural Details

  • Crystal structures solved at 1.85–2.5 Å resolution using WH2–actin–DNase I ternary complexes.
  • Key residue interactions: N-terminal Arg (first WH2 contact with actin); conserved Gly shifts linker position; LKKT motif Leu binds hydrophobic pocket; Lys residues in LKKT may form long-range electrostatic contacts with Asp-24, Asp-25, Glu-99, Glu-100 on actin.
  • WAVE has two Arg in LKKT position (not Lys) — forms salt bridges with actin, explains 5× stronger binding vs WASP.

Relevance to STRC / Hair Cell Biology

Stereocilia are F-actin bundles. Their maintenance depends on actin nucleation, capping, and crosslinking machinery. WH2-containing proteins (WASP, WAVE, spire) are part of the stereocilia actin assembly toolkit. Understanding WH2 biology is foundational to understanding why stereocilia are vulnerable to STRC loss and what nucleation scaffolds maintain their structure. Directly relevant to the question of whether mini-STRC fragments could interfere with or stabilize stereocilia actin organization.

Connections

Graph View

Backlinks