title: CASK point mutation regulates protein-protein interactions and NR2b promoter activity.
abstract: Mutations in the CASK gene result in mental retardation and microcephaly in humans, suggesting an important role for CASK in brain. CASK gene knockout in mice causes neonatal lethality, making further elucidation in mouse models difficult. Because CASK was originally identified as a multidomain adaptor protein, identifying a point mutation interrupting a specific protein interaction would be useful in dissecting its molecular function. Here, a Thr-to-Ala mutation in the rat CASK guanylate kinase (GK) domain was shown to reduce interactions among CASK and Tbr-1 and CINAP, two critical brain proteins. The effect is specific: this mutation does not affect CASK dimerization that occurs via the GK domain. The Tbr-1-CASK-CINAP complex regulates expression of the NMDA receptor subunit 2b (NR2b), and we show that this point mutation also affects NR2b promoter activity. The identification of this mutation may make it possible to further dissect the function of CASK in brain.
authors.affiliation: Graduate Institute of Life Science, National Defense Medical Center, Taipei, 161, Taiwan.
authors.forename: Tzyy-Nan
authors.initials: TN
authors.lastname: Huang
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Hsueh
mesh_terms: D000409:Alanine / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000201:enzymology; D005786:Gene Expression Regulation; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism*
chemical_list: C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D020825:T-Box Domain Proteins; C540454:Tbr1 protein, rat; D013912:Threonine; C106868:CASK kinases; D051528:Guanylate Kinases; D000409:Alanine