Abstract SNACC-37

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Bioinformatic and Structural Analyses of GCOM1 and its Interacting Genes Suggest New Functions

1Roginski R, 2Du P, 3Soteropoulos P, 4Santoiemma P
1PVAMC and Univ of Penn, Philadelphia, PA, USA; 2Rutgers University, Newark, NJ, USA; 3New Jersey Medical School, Newark, NJ, USA; 4Perelman School of Medicine Univ of Pennsylvania, Piscataway, NJ, USA

Since our discovery of the GCOM1 hub gene (1) we have been focusing on its CNS roles, chiefly by finding the genes with which its gene products (termed Gints) interact, and thereby deducing GCOM1's likely functions. Paramount among these interactions is that between GCOM1 and GRIN1 (encoding the NR1 subunit of the NMDA receptor). We showed that anti-GCOM1 antibodies protected neurons against NMDA toxicity (2) and hypothesized that GCOM1 and one or more Gints participate in a novel signal transduction pathway relevant to neuroprotection. To derive more direct evidence for such a pathway, we focused on a key Gint, internexin-[SPCHAR(alpha)] (gene symbol INA; 3), which has already been shown to interact with the NMDAR (4), suggesting a likely pathway of GRIN1> GCOM1> INA> downstream effectors. As an aid to designing our next series of biological experiments, we performed advanced bioinformatic analyses of key GCOM1 and Gint proteins to determine the most likely pathways and structural correlates.
Yeast two hybrid screening which yielded 27 Gints from the Gcom1 cDNA (AY207007) has been described (3). Gcom15 cDNA was derived as described previously (5). The functional analyses were generated through the use of IPA (Ingenuity® Systems, www.ingenuity.com) Core Analysis, which assess over/under representation of signaling and metabolic pathways, molecular networks, and biological processes in the gene lists. The pathways were generated with IPA Path Designer, which builds pathways by connecting molecules and genes if any direct/indirect interaction or regulatory relationship exists between them either in the IPA knowledgebase, or provided by a user. Structural features and relationships were determined by programs from the internet, including Signal P, Motifs, Phyre, protein docking and I-TASSER.
Both Gcom1 and Gcom15 display structural features characteristic of a type I membrane protein with considerable coiled-coil and [SPCHAR(alpha)]-helix structure as in yotiao (AKAP9), which is also an interactor of the NR1 subunit (6), and to which the Gcom1 protein displays similarity (1). Path Designer analysis (IPA knowledgebase with additions from refs 2 and 7) revealed network connections between GRIN1, GCOM1, INA, NSMF and other Gints (Fig 1).
Bioinformatic in silico analyses strongly support our hypothesis that GCOM1 participates in a new pathway that links synaptic activation of NMDARs to changes in neuronal gene expression. This idea is further supported by the fact that the Gcom1 and Gcom15 proteins share two large C-terminal exons with Gdown1, the 13th subunit of RNA polymerase II, whose key role in transcription is currently under intense investigation (8,9).
1.Genomics 2004; 84: 265. 2.NeuroReport 2008; 19: 1721. 3.JNA 2009; 21: 399. 4.Nat Neurosci 2000; 3: 661. 5.ASA Ann Mtg 2010 Abstract A1521. 6.JNeurosci 1998; 18: 2017. 7.Cell 2013; 152: 1119. 8,9.Molec Cell 2012; 45: 38 and 51.

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