WASH and WAVE actin regulators of the Wiskott-Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes

Da Jia, Timothy S. Gomez, Zoltan Metlagel, Junko Umetani, Zbyszek Otwinowski, Michael K. Rosen, Daniel D. Billadeau

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10442-10447
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number23
DOIs
StatePublished - Jun 8 2010

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Wiskott-Aldrich Syndrome Protein Family
Actins
Actin-Related Protein 2-3 Complex
Hereditary Spastic Paraplegia
Transport Vesicles
Endosomes
Amino Acid Sequence
Electrons

Keywords

  • Actin dynamics and capping
  • Endosome
  • Hereditary spastic paraplegia
  • WASH regulatory complex
  • WAVE regulatory complex

ASJC Scopus subject areas

  • General

Cite this

WASH and WAVE actin regulators of the Wiskott-Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes. / Jia, Da; Gomez, Timothy S.; Metlagel, Zoltan; Umetani, Junko; Otwinowski, Zbyszek; Rosen, Michael K.; Billadeau, Daniel D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 23, 08.06.2010, p. 10442-10447.

Research output: Contribution to journalArticle

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abstract = "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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AU - Umetani, Junko

AU - Otwinowski, Zbyszek

AU - Rosen, Michael K.

AU - Billadeau, Daniel D.

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