5io9
From Proteopedia
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| - | ==X-RAY | + | ==X-RAY STRUCTURE OF THE N-TERMINAL DOMAIN OF HUMAN DOUBLECORTIN== |
<StructureSection load='5io9' size='340' side='right' caption='[[5io9]], [[Resolution|resolution]] 1.30Å' scene=''> | <StructureSection load='5io9' size='340' side='right' caption='[[5io9]], [[Resolution|resolution]] 1.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
Revision as of 11:25, 15 December 2016
X-RAY STRUCTURE OF THE N-TERMINAL DOMAIN OF HUMAN DOUBLECORTIN
Structural highlights
Disease[DCX_HUMAN] Defects in DCX are the cause of lissencephaly X-linked type 1 (LISX1) [MIM:300067]; also called X-LIS or LIS. LISX1 is a classic lissencephaly characterized by mental retardation and seizures that are more severe in male patients. Affected boys show an abnormally thick cortex with absent or severely reduced gyri. Clinical manifestations include feeding problems, abnormal muscular tone, seizures and severe to profound psychomotor retardation. Female patients display a less severe phenotype referred to as 'doublecortex'.[1] [2] [3] [4] [5] [6] Defects in DCX are the cause of subcortical band heterotopia X-linked (SBHX) [MIM:300067]; also known as double cortex or subcortical laminar heterotopia (SCLH). SBHX is a mild brain malformation of the lissencephaly spectrum. It is characterized by bilateral and symmetric plates or bands of gray matter found in the central white matter between the cortex and cerebral ventricles, cerebral convolutions usually appearing normal.[7] [8] [9] [10] [11] [12] [13] [14] Note=A chromosomal aberration involving DCX is found in lissencephaly. Translocation t(X;2)(q22.3;p25.1). Function[DCX_HUMAN] Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development. May act by competing with the putative neuronal protein kinase DCLK1 in binding to a target protein. May in that way participate in a signaling pathway that is crucial for neuronal interaction before and during migration, possibly as part of a calcium ion-dependent signal transduction pathway. May be part with PAFAH1B1/LIS-1 of overlapping, but distinct, signaling pathways that promote neuronal migration.[15] Publication Abstract from PubMedDoublecortin is a microtubule-associated protein produced during neurogenesis. The protein stabilizes microtubules and stimulates their polymerization which allows migration of immature neurons to their designated location in the brain. Mutations in the gene that impair doublecortin function and cause severe brain formation disorders are located on a tandem repeat of two doublecortin domains. The molecular mechanism of action of doublecortin is only incompletely understood. Anti-doublecortin antibodies such as the rabbit polyclonal Abcam 18732 are widely used as neurogenesis markers. Here, we report the generation and characterization of antibodies that bind to single doublecortin domains. The antibodies were used as tools to obtain structures of both domains. Four independent crystal structures of the N-terminal domain reveal several distinct open and closed conformations of the peptide linking N- and C-terminal domains which can be related to doublecortin function. An NMR assignment and a crystal structure in complex with a camelid antibody fragment show that the doublecortin C-terminal domain adopts the same well defined ubiquitin like fold as the N-terminal domain, despite its reported aggregation and molten globule like properties. The antibodies' unique domain specificity also renders them ideal research tools to better understand the role of individual domains in doublecortin function. A single chain camelid antibody fragment specific for the C-terminal doublecortin domain affected microtubule binding whereas a monoclonal mouse antibody specific for the N-terminal domain did not. Together with steric considerations this suggests the microtubule interacting doublecortin domain observed in cryo-electron micrographs to be the C-terminal domain rather than the N-terminal. Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies.,Burger D, Stihle M, Sharma A, Di Lello P, Benz J, D'Arcy B, Debulpaep M, Fry D, Huber W, Kremer T, Laeremans T, Matile H, Ross A, Rufer AC, Schoch G, Steinmetz MO, Steyaert J, Rudolph MG, Thoma R, Ruf A J Biol Chem. 2016 May 10. pii: jbc.M116.726547. PMID:27226599[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Arcy, B D | Benz, J | Burger, D | Debulpaep, M | Fry, D | Huber, W | Kremer, T | Laeremans, T | Lello, P Di | Matile, H | Ross, A | Rudolph, M G | Ruf, A | Rufer, A C | Schoch, G | Sharma, A | Steinmetz, M O | Steyaert, J | Stihle, M | Thoma, R | Dcx domain | Microtubule associated | Signaling protein | Transferase | Ubiquitin-like fold
