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Structure, function and regulation of WASH actin regulatory complex

Da Jia Research

While working in Rosen lab, I discovered a novel actin regulatory assembly, the WASH Regulatory Complex (SHRC). WASH is a recently discovered member of the Wiskott–Aldrich Syndrome Protein (WASP) family, which stimulates Arp2/3-mediated actin nucleation via a conserved C-terminal VCA element.

The activity of VCA is inhibited within the SHRC, which consists of four other core subunits in addition to WASH: FAM21, Strumpellin, SWIP, and CCDC53. The CapZ dimer also associates with the complex by interacting with the C-terminus of FAM21. Following reconstitution of the SHRC from insect cells, I elucidated its organizational architecture through bioinformatic, biochemical and electron microscopic analyses, and showed that it is distantly related to the well-known WAVE Regulatory Complex.

In the cell, WASH regulates actin dynamics on endosomes and controls intracellular trafficking. I defined the molecular mechanism by which the SHRC is targeted to endosomes. The SHRC subunit, FAM21, directly interacts with the cargo-selective complex (CSC) of the retromer. Endosomal localization of SHRC is CSC-dependent and relies on multivalency of FAM21 repeat elements.

My current research focuses on how the SHRC is regulated and how WASH-mediated actin polymerization controls retromer biology.

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