Hierarchical Regulation of WASP/WAVE Proteins

Shae B. Padrick; Hui Chun Cheng; Ayman M. Ismail; Sanjay C. Panchal; Lynda K. Doolittle; Soyeon Kim; Brian M. Skehan; Junko Umetani; Chad A Brautigam; John M. Leong; Michael K Rosen

doi:10.1016/j.molcel.2008.10.012

Hierarchical Regulation of WASP/WAVE Proteins

Shae B. Padrick, Hui Chun Cheng, Ayman M. Ismail, Sanjay C. Panchal, Lynda K. Doolittle, Soyeon Kim, Brian M. Skehan, Junko Umetani, Chad A Brautigam, John M. Leong, Michael K Rosen

Research output: Contribution to journal › Article › peer-review

165 Scopus citations

Abstract

Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an additional level of regulation that is superimposed upon allostery: dimerization increases the affinity of active WASP species for Arp2/3 complex by up to 180-fold, greatly enhancing actin assembly by this system. This finding explains a large and apparently disparate set of observations under a common mechanistic framework. These include WASP activation by the bacterial effector EspFu and a large number of SH3 domain proteins, the effects on WASP of membrane localization/clustering and assembly into large complexes, and cooperativity between different family members. Allostery and dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses.

Original language	English (US)
Pages (from-to)	426-438
Number of pages	13
Journal	Molecular cell
Volume	32
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2008.10.012
State	Published - Nov 7 2008

Keywords

CELLBIO
PROTEINS

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2008.10.012

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@article{11f70706286b4abb82418c8da16ae7a6,

title = "Hierarchical Regulation of WASP/WAVE Proteins",

abstract = "Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an additional level of regulation that is superimposed upon allostery: dimerization increases the affinity of active WASP species for Arp2/3 complex by up to 180-fold, greatly enhancing actin assembly by this system. This finding explains a large and apparently disparate set of observations under a common mechanistic framework. These include WASP activation by the bacterial effector EspFu and a large number of SH3 domain proteins, the effects on WASP of membrane localization/clustering and assembly into large complexes, and cooperativity between different family members. Allostery and dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses.",

keywords = "CELLBIO, PROTEINS",

author = "Padrick, {Shae B.} and Cheng, {Hui Chun} and Ismail, {Ayman M.} and Panchal, {Sanjay C.} and Doolittle, {Lynda K.} and Soyeon Kim and Skehan, {Brian M.} and Junko Umetani and Brautigam, {Chad A} and Leong, {John M.} and Rosen, {Michael K}",

note = "Funding Information: We thank Dr. Luke Rice and Pilong Li for advice regarding modeling, Tim Craig and Drs. Joe Albanesi and Elliott Ross for assistance with lipid experiments, Dr. Hongtao Yu for assistance with cell culture, Dr. Tom Wandless for providing rapamycin, Drs. Daisy Leung and Xiaolan Yao for providing mTOR and FKBP expression constructs, Chinatsu Otomo for cloning assistance, and Dr. Tom Pollard for critical review of the manuscript. This work was supported by the Howard Hughes Medical Institute and grants from the National Institutes of Health (NIH-R01-GM56322 to M.K.R.; NIH-R01-AI46454 to J.M.L.) and the Welch Foundation (I-1544 to M.K.R.). S.B.P. and H.-C.C. were supported by fellowships from the NIH (1F32-GM06917902), and the Chilton Foundation, respectively. ",

year = "2008",

month = nov,

day = "7",

doi = "10.1016/j.molcel.2008.10.012",

language = "English (US)",

volume = "32",

pages = "426--438",

journal = "Molecular cell",

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T1 - Hierarchical Regulation of WASP/WAVE Proteins

AU - Padrick, Shae B.

AU - Cheng, Hui Chun

AU - Ismail, Ayman M.

AU - Panchal, Sanjay C.

AU - Doolittle, Lynda K.

AU - Kim, Soyeon

AU - Skehan, Brian M.

AU - Umetani, Junko

AU - Brautigam, Chad A

AU - Leong, John M.

AU - Rosen, Michael K

N1 - Funding Information: We thank Dr. Luke Rice and Pilong Li for advice regarding modeling, Tim Craig and Drs. Joe Albanesi and Elliott Ross for assistance with lipid experiments, Dr. Hongtao Yu for assistance with cell culture, Dr. Tom Wandless for providing rapamycin, Drs. Daisy Leung and Xiaolan Yao for providing mTOR and FKBP expression constructs, Chinatsu Otomo for cloning assistance, and Dr. Tom Pollard for critical review of the manuscript. This work was supported by the Howard Hughes Medical Institute and grants from the National Institutes of Health (NIH-R01-GM56322 to M.K.R.; NIH-R01-AI46454 to J.M.L.) and the Welch Foundation (I-1544 to M.K.R.). S.B.P. and H.-C.C. were supported by fellowships from the NIH (1F32-GM06917902), and the Chilton Foundation, respectively.

PY - 2008/11/7

Y1 - 2008/11/7

N2 - Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an additional level of regulation that is superimposed upon allostery: dimerization increases the affinity of active WASP species for Arp2/3 complex by up to 180-fold, greatly enhancing actin assembly by this system. This finding explains a large and apparently disparate set of observations under a common mechanistic framework. These include WASP activation by the bacterial effector EspFu and a large number of SH3 domain proteins, the effects on WASP of membrane localization/clustering and assembly into large complexes, and cooperativity between different family members. Allostery and dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses.

AB - Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an additional level of regulation that is superimposed upon allostery: dimerization increases the affinity of active WASP species for Arp2/3 complex by up to 180-fold, greatly enhancing actin assembly by this system. This finding explains a large and apparently disparate set of observations under a common mechanistic framework. These include WASP activation by the bacterial effector EspFu and a large number of SH3 domain proteins, the effects on WASP of membrane localization/clustering and assembly into large complexes, and cooperativity between different family members. Allostery and dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses.

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KW - PROTEINS

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DO - 10.1016/j.molcel.2008.10.012

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AN - SCOPUS:55049090663

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SP - 426

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JO - Molecular cell

JF - Molecular cell

IS - 3

ER -

Hierarchical Regulation of WASP/WAVE Proteins

Abstract

Keywords

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