Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 23, Pages 10442-10447Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0913293107
Keywords
actin dynamics and capping; endosome; WAVE regulatory complex; WASH regulatory complex; hereditary spastic paraplegia
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Funding
- Mayo Foundation
- Howard Hughes Medical Institute
- National Institutes of Health [R01-AI065474, R01-GM056322]
- Welch Foundation [Grant I-1544]
- Allergic Diseases Training Grant [NIH-T32-AI07047]
- Cancer Research Institute Fellowship
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We recently showed that the Wiskott-Aldrich syndrome protein (WASP) family member, WASH, localizes to endosomal subdomains and regulates endocytic vesicle scission in an Arp2/3-dependent manner. Mechanisms regulating WASH activity are unknown. Here we show that WASH functions in cells within a 500 kDa core complex containing Strumpellin, FAM21, KIAA1033 (SWIP), and CCDC53. Although recombinant WASH is constitutively active toward the Arp2/3 complex, the reconstituted core assembly is inhibited, suggesting that it functions in cells to regulate actin dynamics through WASH. FAM21 interacts directly with CAPZ and inhibits its actin-capping activity. Four of the five core components show distant (approximately 15% amino acid sequence identify) but significant structural homology to components of a complex that negatively regulates the WASP family member, WAVE. Moreover, biochemical and electron microscopic analyses show that the WASH and WAVE complexes are structurally similar. Thus, these two distantly related WASP family members are controlled by analogous structurally related mechanisms. Strumpellin is mutated in the human disease hereditary spastic paraplegia, and its link to WASH suggests that misregulation of actin dynamics on endosomes may play a role in this disorder.
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