The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications.
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.
Kim
Myung Hee
MH
Department of Molecular Physiology and Biological Physics and Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
Cooper
David R
DR
Oleksy
Arkadiusz
A
Devedjiev
Yancho
Y
Derewenda
Urszula
U
Reiner
Orly
O
Otlewski
Jacek
J
Derewenda
Zygmunt S
ZS
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000494:pharmacology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D019791:Guanidine