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8fdu

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Engineered human dynein motor domain in the microtubule-unbound state with LIS1 complex in the buffer containing ATP-Vi (local refined on AAA3-AAA5 and LIS1)

Structural highlights

8fdu is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.3Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LIS1_HUMAN Miller-Dieker syndrome;Subcortical band heterotopia;Lissencephaly due to LIS1 mutation;17p13.3 microduplication syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

LIS1_HUMAN 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). 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 (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. May also play a role in other forms of cell locomotion including the migration of fibroblasts during wound healing. Required for dynein recruitment to microtubule plus ends and BICD2-bound cargos (PubMed:22956769). May modulate the Reelin pathway through interaction of the PAF-AH (I) catalytic dimer with VLDLR (By similarity).[UniProtKB:P43033][UniProtKB:P63005]^[1] ^[2]

References

↑ 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
↑ Splinter D, Razafsky DS, Schlager MA, Serra-Marques A, Grigoriev I, Demmers J, Keijzer N, Jiang K, Poser I, Hyman AA, Hoogenraad CC, King SJ, Akhmanova A. BICD2, dynactin, and LIS1 cooperate in regulating dynein recruitment to cellular structures. Mol Biol Cell. 2012 Nov;23(21):4226-41. PMID:22956769 doi:10.1091/mbc.E12-03-0210