We have isolated the cDNA for a tyrosine kinase receptor that is expressed in the nervous system of Aplysia californica and that is similar to the vertebrate insulin receptor. Binding studies and immunocytochemical staining show that the receptor is abundant in the bag cell neurons. Application of vertebrate insulin to clusters of bag cell neurons stimulates the phosphorylation of the receptor on tyrosine residues, and exposure of isolated bag cell neurons to insulin produces an increase in height and a decrease in duration of the action potentials that can be detected within 15-30 min. These effects were not seen with insulin-like growth factor-1. In voltage-clamped neurons, insulin produces an increase in the amplitude of the voltage-dependent Ca2+ current that can be blocked by preincubation with herbimycin A, an inhibitor of tyrosine kinases. Insulin also enhances a delayed K+ current. We suggest that insulin-like peptides regulate the excitability of the bag cell neurons.
Protein methylation on arginine and lysine residues is emerging to be an important post-translational modification in eukaryotes. The methylation affects interaction of target protein with other molecules, regulating cellular processes such as RNA processing and/or transport, chromatin structure and gene transcription. Protein arginine (R) methyltransferases (PRMT) have up to 8 members in human. PRMT1 is the predominant PRMT in mammal, accounting for 85% of the cellular PRMT activity and is essential for early postimplantation development in mouse. Here we describe the crystal structures of rat PRMT1 in complex with peptides containing single or three arginines, respectively. The results reveal a two-domain structure-an AdoMet-binding domain and a barrel-like domain-with the active site pocket located in between the two domains. Mutagenesis studies confirmed that two glutamic acids in the active site are essential for enzymatic activity and the dimerization of PRMT is essential for methyl donor AdoMet binding. Three peptide-binding channels are identified. The multiple peptide binding channels are probably important for binding of PRMT1 substrates that often contain multiple arginines in RGG or RXR contexts. Protein lysine (K) methyltransferases (PKMT) belong to a rapidly growing family of enzymes that methylates specific lysines on histone tails. Histone methylation is an integral part of the 'histone code' that regulates the transcriptional accessibility of chromatin. We will present the first structure of a PKMT, discuss the role of conserved sequence motifs within the PKMT, particularly the SET domain that is widely spread among many proteins associated with chromatin function.
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