title: Entamoeba histolytica RacC selectively engages p21-activated kinase effectors.
abstract: Rho family GTPases modulate actin cytoskeleton dynamics by signaling through multiple effectors, including the p21-activated kinases (PAKs). The intestinal parasite Entamoeba histolytica expresses ∼20 Rho family GTPases and seven isoforms of PAK, two of which have been implicated in pathogenesis-related processes such as amoebic motility and invasion and host cell phagocytosis. Here, we describe two previously unstudied PAK isoforms, EhPAK4 and EhPAK5, as highly specific effectors of EhRacC. A structural model based on 2.35 Å X-ray crystallographic data of a complex between EhRacC(Q65L)·GTP and the EhPAK4 p21 binding domain (PBD) reveals a fairly well-conserved Rho/effector interface despite deviation of the PBD α-helix. A structural comparison with EhRho1 in complex with EhFormin1 suggests likely determinants of Rho family GTPase signaling specificity in E. histolytica. These findings suggest a high degree of Rho family GTPase diversity and specificity in the single-cell parasite E. histolytica. Because PAKs regulate pathogenesis-related processes in E. histolytica, they may be valid pharmacologic targets for anti-amoebiasis drugs.
authors.affiliation: Department of Pharmacology, The University of North Carolina , Chapel Hill, North Carolina 27514, United States.
authors.forename: Dustin E
authors.initials: DE
authors.lastname: Bosch
authors.forename: David P
authors.initials: DP
authors.lastname: Siderovski
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004748:Entamoeba histolytica / Q000737:chemistry / Q000201:enzymology*; D004749:Entamoebiasis / Q000469:parasitology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000737:chemistry / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins