Histone acetylation plays a critical role during long-term memory formation. Several studies have demonstrated that the histone acetyltransferase (HAT) CBP is required during long-term memory formation, but the involvement of other HAT proteins has not been extensively investigated. The HATs CBP and p300 have at least 400 described interacting proteins including transcription factors known to play a role in long-term memory formation. Thus, CBP and p300 constitute likely candidates for transcriptional coactivators in memory formation. In this study, we took a loss-of-function approach to evaluate the role of p300 in long-term memory formation. We used conditional knock-out mice in which the deletion of p300 is restricted to the postnatal phase and to subregions of the forebrain. We found that p300 is required for the formation of long-term recognition memory and long-term contextual fear memory in the CA1 area of the hippocampus and cortical areas.

Although it is well established that RhoA signaling pathways play key roles in regulating neuronal morphology, their involvement in other aspects of neuronal function has received little attention. Recent studies have elucidated a novel intracellular signaling pathway used by RhoA to elicit activation of serum response factor (SRF)-mediated transcription. In this pathway, activation of RhoA triggers nuclear translocation of the SRF co-activator, megakaryocytic acute leukemia (MAL). In assessing whether RhoA regulates transcription in neurons via this pathway, we have found that a constitutively active form of Tech (transcript-enriched in cortex and hippocampus), a RhoA guanine nucleotide exchange factor (GEF) that is expressed in forebrain neurons, stimulates SRF reporter activity in extracts of primary cortical cultures and induces nuclear translocation of MAL in cortical neurons. Both of these responses appear to be mediated by Tech's activation of RhoA as they are not mimicked by a mutant Tech construct lacking RhoA GEF activity and are blocked by C3 transferase, a selective inhibitor of RhoA. Furthermore, Techinduced increases in SRF activity are suppressed by a dominant negative MAL construct. These findings demonstrate that RhoA signaling pathways are able to regulate transcription in neurons by triggering translocation of the SRF co-activator MAL.

AutDB is a deeply annotated resource for exploring the impact of genetic variations associated with autism spectrum disorders (ASD). First released in 2007, AutDB has evolved into a multi-modular resource of diverse types of genetic and functional evidence related to ASD. Current modules include: Human Gene, which annotates all ASD-linked genes and their variants; Animal Model, which catalogs behavioral, anatomical and physiological data from rodent models of ASD; Protein Interaction (PIN), which builds interactomes from direct relationships of protein products of ASD genes; and Copy Number Variant (CNV), which catalogs deletions and duplications of chromosomal loci identified in ASD. A multilevel data-integration strategy is utilized to connect the ASD genes to the components of the other modules. All information in this resource is manually curated by expert scientists from primary scientific publications and is referenced to source articles. AutDB is actively maintained with a rigorous quarterly data release schedule. As of June 2017, AutDB contains detailed annotations for 910 genes, 2197 CNV loci, 1060 rodent models and 38 296 PINs. With its widespread use by the research community, AutDB serves as a reference resource for analysis of large datasets, accelerating ASD research and potentially leading to targeted drug treatments. AutDB is available at http://autism.mindspec.org/autdb/Welcome.do.

Fumarase catalyzes the reversible conversion of fumarate to S-malate during the operation of the ubiquitous Kreb's cycle. Previous studies have shown that the active site includes side chains from three of the four subunits within the tetrameric enzyme. We used a clinically observed human mutation to narrow our search for potential catalytic groups within the fumarase active site. Offspring homozygous for the missense mutation, a G-955-C transversion in the fumarase gene, results in the substitution of a glutamine at amino acid 319 for the normal glutamic acid. To more fully understand the implications of this mutation, a single-step site-directed mutagenesis method was used to generate the homologous substitution at position 315 within fumarase C from Escherichia coli. Subsequent kinetic and X-ray crystal structure analyses show changes in the turnover number and the cocrystal structure with bound citrate.Keywords: Fumarase; active site; Kreb's cycle; homology; metabolic disease FumarasesFumarase enzymes catalyze the reversible hydration/dehydration of fumarate to S-malate. Prokaroytes have three forms of fumarase, fumarase A, fumarase B, and fumarase C (FumC), and each has been classified as either class I or class II, depending on their relative subunit arrangement, metal requirement, and thermal stability. FumC belongs to the class II-type fumarases, which are iron-independent, thermal-stable, tetrameric enzymes of 200,000 D harboring three distinct segments of amino acids with significant homology. It is the focus of this study. Class I fumarases are heat-labile, superoxide anion radical (O 2 − )-sensitive, Fe 2+ -dependent, dimeric proteins of 120 kD. Fumarase A and fumarase B from Escherichia coli (E. coli) are examples of class I fumarases.There are two types of fumarase found within human tissues, cytosolic and mitochondrial, and both share sequence identity to FumC from E. coli (Woods et al. 1986). The mitochondrial form is responsible for the reversible conversion of fumarate to S-malate during operation of the Kreb's cycle, whereas the cytosolic form metabolizes fumarate, a by-product of the urea cycle. SuperfamilyAmino acid identity within the class II fumarase family is quite high, 59% between FumC from E. coli and human fumarase (Woods et al. 1986). In addition, this classification shows an elevated level of identity within three specific regions. Region 1 spans His 129 through Thr 146, region 2 Val 182 through Glu 200, and region 3 Gly 317 through Glu 331 (all amino-acid numbering is based on the FumC amino acid sequence unless otherwise noted).FumC was the first class II fumarase enzyme structure to be solved, and its active site was shown to harbor many of the amino acids within the three highly conserved regions (Weaver et al. 1995). In particular, homology between Gly Reprint requests to: Dr. Todd M. Weaver, University of Wisconsin-La Crosse, Department of Chemistry, La Crosse, WI 54601, USA; e-mail: weaver.todd@uwlax.edu; fax: (608) 785-8281.Abbreviations: Ni 2+-NTA, nickel nitrotril...