Inhibition of Scar by the HEM2/Abi2/Pir121 Complex

University Of Texas Sw Med Ctr/Dallas, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): Scar, a WASP family protein, integrates signals from proteins such as Rac and Nck and regulates the formation of actin structures such as lamellipodia. As defines the WASP family, Scar has a C-terminal VCA domain, which activates the Arp2/3 complex, resulting in the nucleation of actin fibers. Scar, however, lacks the intramolecular autoinhibition domain of WASP and N-WASP, and appears to be constitutively active in isolation. The regulation of Scar by Rac and Nck has recently been shown to involve a multiprotein complex, HEM2/Abi2/Pir121 (HAP), which inhibits the activity of Scar. In contrast to WASP, Scar is activated by relief of intermolecular binding/inhibition by HAP, not intramolecular regulation. A biochemical and structural model of inhibition of Scar by HAP will give valuable insight into the integration of numerous signals into a cellular response. A principal step in explaining Scar regulation by HAP is to carefully define the binding site of HAP on Scar. Through use of Scar truncations, the domain level structural elements needed for inhibition by HAP will be defined. NMR line broadening experiments will then determine the binding site in terms of specific amino acids and the site will be confirmed by designed point mutants testing the HAP or Arp2/3 binding interfaces.