title: Coupling PAF signaling to dynein regulation: structure of LIS1 in complex with PAF-acetylhydrolase.
abstract: Mutations in the LIS1 gene cause lissencephaly, a human neuronal migration disorder. LIS1 binds dynein and the dynein-associated proteins Nde1 (formerly known as NudE), Ndel1 (formerly known as NUDEL), and CLIP-170, as well as the catalytic alpha dimers of brain cytosolic platelet activating factor acetylhydrolase (PAF-AH). The mechanism coupling the two diverse regulatory pathways remains unknown. We report the structure of LIS1 in complex with the alpha2/alpha2 PAF-AH homodimer. One LIS1 homodimer binds symmetrically to one alpha2/alpha2 homodimer via the highly conserved top faces of the LIS1 beta propellers. The same surface of LIS1 contains sites of mutations causing lissencephaly and overlaps with a putative dynein binding surface. Ndel1 competes with the alpha2/alpha2 homodimer for LIS1, but the interaction is complex and requires both the N- and C-terminal domains of LIS1. Our data suggest that the LIS1 molecule undergoes major conformational rearrangement when switching from a complex with the acetylhydrolase to the one with Ndel1.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Cataldo
authors.initials: C
authors.lastname: Tarricone
authors.forename: Franco
authors.initials: F
authors.lastname: Perrina
authors.forename: Silvia
authors.initials: S
authors.lastname: Monzani
authors.forename: Lucia
authors.initials: L
authors.lastname: Massimiliano
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Kim
authors.forename: Zygmunt S
authors.initials: ZS
authors.lastname: Derewenda
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004398:Dyneins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010972:Platelet Activating Factor / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D018411:Spodoptera
chemical_list: D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; C486015:Ndel1 protein, mouse; D010972:Platelet Activating Factor; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse; D004398:Dyneins