title: D186/D190 is an allele-dependent determinant of HIV-1 Nef function.
abstract: The HIV-1 pathogenesis factor Nef interacts with numerous ligands to affect cellular vesicular transport, signal transduction and cytoskeletal dynamics. While most Nef functions depend on multivalent protein interaction motifs, disrupting actin dynamics requires a motif that specifically recruits the host kinase PAK2. An adjacent aspartate was recently predicted to mediate Nef-β-catenin interactions. We report here that β-catenin can be co-immunoprecipitated with Nef.GFP from Jurkat T cell lysates. This association is conserved among lentiviral Nef proteins but does not involve classical Nef protein interaction motifs, including the critical aspartate. While aspartate-to-alanine mutations impaired cell surface receptor downregulation and interference with actin dynamics and cell motility by HIV-1 NA7 Nef, analogous mutations did not affect HIV-1 SF2 Nef function. These allelic differences were determined by a proximal lysine/arginine polymorphism. These results emphasize differences between Nef alleles regarding the functional role of individual residues and underscore the need for allele-specific structure-function analyses.
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Andrea
authors: A
authors: Imle
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Bettina
authors: B
authors: Stolp
authors: Institute for Cell Biology, University of Münster, Münster, Germany.
authors: Verena
authors: V
authors: Böhmer
authors: Institute of Innate Immunity, Department of Structural Immunology, Bonn, Germany.
authors: Matthias
authors: M
authors: Geyer
authors: Institute for Cell Biology, University of Münster, Münster, Germany.
authors: Erez
authors: E
authors: Raz
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: oliver.fackler@med.uni-heidelberg.de.
authors: Oliver T
authors: OT
authors: Fackler
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011956:Receptors, Cell Surface / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054462:p21-Activated Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D011956:Receptors, Cell Surface; D051176:beta Catenin; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases
keywords: HIV-1 Nef; PAK2; Protein interaction; β-catenin