1uuj is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
LIS1_MOUSE Regulatory subunit (beta subunit) of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)), an enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and participates in PAF inactivation. Regulates the PAF-AH (I) activity in a catalytic dimer composition-dependent manner (By similarity). Positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus end. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the peripheral transport of microtubule fragments and the coupling of the nucleus and centrosome. Required during brain development for the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Neuronal migration involves a process called nucleokinesis, whereby migrating cells extend an anterior process into which the nucleus subsequently translocates. During nucleokinesis dynein at the nuclear surface may translocate the nucleus towards the centrosome by exerting force on centrosomal microtubules. Also required for proper activation of Rho GTPases and actin polymerization at the leading edge of locomoting cerebellar neurons and postmigratory hippocampal neurons in response to calcium influx triggered via NMDA receptors. May also play a role in other forms of cell locomotion including the migration of fibroblasts during wound healing. Non-catalytic subunit of an acetylhydrolase complex which inactivates platelet-activating factor (PAF) by removing the acetyl group at the SN-2 position. Required for dynein recruitment to microtubule plus ends and BICD2-bound cargos (By similarity). May modulate the Reelin pathway through interaction of the PAF-AH (I) catalytic dimer with VLDLR (PubMed:17330141).[UniProtKB:P43033][UniProtKB:P43034][HAMAP-Rule:MF_03141][1][2][3][4][5][6][7][8][9][10][11][12][13][14]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mutations in the Lis1 gene result in lissencephaly (smooth brain), a debilitating developmental syndrome caused by the impaired ability of postmitotic neurons to migrate to their correct destination in the cerebral cortex. Sequence similarities suggest that the LIS1 protein contains a C-terminal seven-blade beta-propeller domain, while the structure of the N-terminal fragment includes the LisH (Lis-homology) motif, a pattern found in over 100 eukaryotic proteins with a hitherto unknown function. We present the 1.75 A resolution crystal structure of the N-terminal domain of mouse LIS1, and we show that the LisH motif is a novel, thermodynamically very stable dimerization domain. The structure explains the molecular basis of a low severity form of lissencephaly.
The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications.,Kim MH, Cooper DR, Oleksy A, Devedjiev Y, Derewenda U, Reiner O, Otlewski J, Derewenda ZS Structure. 2004 Jun;12(6):987-98. PMID:15274919[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Smith DS, Niethammer M, Ayala R, Zhou Y, Gambello MJ, Wynshaw-Boris A, Tsai LH. Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nat Cell Biol. 2000 Nov;2(11):767-75. PMID:11056530 doi:10.1038/35041000
↑Cahana A, Escamez T, Nowakowski RS, Hayes NL, Giacobini M, von Holst A, Shmueli O, Sapir T, McConnell SK, Wurst W, Martinez S, Reiner O. Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6429-34. PMID:11344260 doi:10.1073/pnas.101122598
↑Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL, Ayala R, Tsai LH, Dobyns W, Ledbetter D, Hirotsune S, Wynshaw-Boris A. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet. 2003 Jul;34(3):274-85. PMID:12796778 doi:https://dx.doi.org/10.1038/ng1169
↑Tokuoka SM, Ishii S, Kawamura N, Satoh M, Shimada A, Sasaki S, Hirotsune S, Wynshaw-Boris A, Shimizu T. Involvement of platelet-activating factor and LIS1 in neuronal migration. Eur J Neurosci. 2003 Aug;18(3):563-70. PMID:12911752 doi:10.1046/j.1460-9568.2003.02778.x
↑Kholmanskikh SS, Dobrin JS, Wynshaw-Boris A, Letourneau PC, Ross ME. Disregulated RhoGTPases and actin cytoskeleton contribute to the migration defect in Lis1-deficient neurons. J Neurosci. 2003 Sep 24;23(25):8673-81. PMID:14507966 doi:10.1523/JNEUROSCI.23-25-08673.2003
↑Assadi AH, Zhang G, Beffert U, McNeil RS, Renfro AL, Niu S, Quattrocchi CC, Antalffy BA, Sheldon M, Armstrong DD, Wynshaw-Boris A, Herz J, D'Arcangelo G, Clark GD. Interaction of reelin signaling and Lis1 in brain development. Nat Genet. 2003 Nov;35(3):270-6. PMID:14578885 doi:10.1038/ng1257
↑Dujardin DL, Barnhart LE, Stehman SA, Gomes ER, Gundersen GG, Vallee RB. A role for cytoplasmic dynein and LIS1 in directed cell movement. J Cell Biol. 2003 Dec 22;163(6):1205-11. PMID:14691133 doi:10.1083/jcb.200310097
↑Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, Gleeson JG. Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J Cell Biol. 2004 Jun 7;165(5):709-21. PMID:15173193 doi:10.1083/jcb.200309025
↑Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG, Tsai LH. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron. 2004 Oct 14;44(2):263-77. doi: 10.1016/j.neuron.2004.09.030. PMID:15473966 doi:https://dx.doi.org/10.1016/j.neuron.2004.09.030
↑Sasaki S, Mori D, Toyo-oka K, Chen A, Garrett-Beal L, Muramatsu M, Miyagawa S, Hiraiwa N, Yoshiki A, Wynshaw-Boris A, Hirotsune S. Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality. Mol Cell Biol. 2005 Sep;25(17):7812-27. doi: 10.1128/MCB.25.17.7812-7827.2005. PMID:16107726 doi:https://dx.doi.org/10.1128/MCB.25.17.7812-7827.2005
↑Toyo-Oka K, Sasaki S, Yano Y, Mori D, Kobayashi T, Toyoshima YY, Tokuoka SM, Ishii S, Shimizu T, Muramatsu M, Hiraiwa N, Yoshiki A, Wynshaw-Boris A, Hirotsune S. Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration. Hum Mol Genet. 2005 Nov 1;14(21):3113-28. Epub 2005 Oct 3. PMID:16203747 doi:https://dx.doi.org/ddi339
↑Kholmanskikh SS, Koeller HB, Wynshaw-Boris A, Gomez T, Letourneau PC, Ross ME. Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility. Nat Neurosci. 2006 Jan;9(1):50-7. PMID:16369480 doi:10.1038/nn1619
↑Mesngon MT, Tarricone C, Hebbar S, Guillotte AM, Schmitt EW, Lanier L, Musacchio A, King SJ, Smith DS. Regulation of cytoplasmic dynein ATPase by Lis1. J Neurosci. 2006 Feb 15;26(7):2132-9. PMID:16481446 doi:10.1523/JNEUROSCI.5095-05.2006
↑Zhang G, Assadi AH, McNeil RS, Beffert U, Wynshaw-Boris A, Herz J, Clark GD, D'Arcangelo G. The Pafah1b complex interacts with the reelin receptor VLDLR. PLoS One. 2007 Feb 28;2(2):e252. PMID:17330141 doi:10.1371/journal.pone.0000252
↑Kim MH, Cooper DR, Oleksy A, Devedjiev Y, Derewenda U, Reiner O, Otlewski J, Derewenda ZS. The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications. Structure. 2004 Jun;12(6):987-98. PMID:15274919 doi:10.1016/j.str.2004.03.024
