TY - JOUR
T1 - WASH and WAVE actin regulators of the Wiskott-Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes
AU - Jia, Da
AU - Gomez, Timothy S.
AU - Metlagel, Zoltan
AU - Umetani, Junko
AU - Otwinowski, Zbyszek
AU - Rosen, Michael K.
AU - Billadeau, Daniel D.
PY - 2010/6/8
Y1 - 2010/6/8
N2 - 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.
AB - 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.
KW - Actin dynamics and capping
KW - Endosome
KW - Hereditary spastic paraplegia
KW - WASH regulatory complex
KW - WAVE regulatory complex
UR - http://www.scopus.com/inward/record.url?scp=77953757324&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953757324&partnerID=8YFLogxK
U2 - 10.1073/pnas.0913293107
DO - 10.1073/pnas.0913293107
M3 - Article
C2 - 20498093
AN - SCOPUS:77953757324
SN - 0027-8424
VL - 107
SP - 10442
EP - 10447
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
ER -