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.
authors.affiliation: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shae B
authors.initials: SB
authors.lastname: Padrick
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Cheng
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Ismail
authors.forename: Sanjay C
authors.initials: SC
authors.lastname: Panchal
authors.forename: Lynda K
authors.initials: LK
authors.lastname: Doolittle
authors.forename: Soyeon
authors.initials: S
authors.lastname: Kim
authors.forename: Brian M
authors.initials: BM
authors.lastname: Skehan
authors.forename: Junko
authors.initials: J
authors.lastname: Umetani
authors.forename: Chad A
authors.initials: CA
authors.lastname: Brautigam
authors.forename: John M
authors.initials: JM
authors.lastname: Leong
authors.forename: Michael K
authors.initials: MK
authors.lastname: Rosen
mesh_terms: D000199:Actins / Q000378:metabolism; D000494:Allosteric Regulation; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D019281:Dimerization; D006706:Homeostasis; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D011487:Protein Conformation; D017510:Protein Folding; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics* / Q000378:metabolism*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000199:Actins; C114864:WASF1 protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D051300:Wiskott-Aldrich Syndrome Protein Family