Proteins modulating TRP channel function
Introduction
Signaling of hormones across the plasma membrane is mediated by macromolecular complexes composed of different proteins (for review see [1], [2], [3]). In these macromolecular structures different proteins, i.e. receptors, channels or enzymes, are brought into vicinity to each other. The organization of proteins by structure-forming proteins speeds up the transmembrane signaling. The components of the complexes assemble directly after protein synthesis, and the proteins are translocated in preformed complexes to their cellular target compartment. The macromolecular structure is formed by scaffold proteins which share characteristic sequences. The peptide chains contain domains that mediate protein–protein interaction. Different domains important for protein–protein interaction, such as PDZ, ankyrin repeat, SH3, WW, and proline-rich domains, have been described (for review see [1], [4], [5]). The specificity of the interaction depends on the sequence of the protein domains forming the interfaces. Parallel to the permanent constituents of the complexes, additional proteins, such as calcium-binding proteins, kinases, and GTPases, can temporarily interact with single particular proteins to modulate the complex activity.
The occurrence of ankyrin repeat domains has been shown in many TRP channels [6]. Ankyrin repeat domains link proteins, i.e. inositol-1,4,5-trisphosphate (InsP3) receptor or Na+/H+-exchanger, to the cytoskeleton (for review see [7]). The occurrence of ankyrin repeat domains is differently pronounced within the three families of TRP channels. Within the members of the vanilloid-like family (TRPV), the cytosolic N-terminal sequences carry domains with the highest score of probability to function as ankyrin repeat domains, whereas this probability is reduced for the sequences of the classical TRP channel family (TRPC). In the unique N-terminal sequences of the melastatin-like subfamily (TRPM), only a few amino acids of the ankyrin repeat domain signature can be found, too little to predict an ankyrin repeat domain function. The function of the ankyrin repeat domains for TRP channels is poorly understood. Apart from that, analysis of protein sequences does not give any hints indicating that known functional domains are present in mammalian TRP channels. In contrast, the data on Drosophila phototransduction demonstrated the involvement of PDZ domains and calmodulin in TRP channel regulation (see below).
Section snippets
Calcium-binding proteins
The Drosophila TRP-like channel (TRPL) was identified in a screen searching for calmodulin-binding proteins [8]. The possible influence of calcium-binding proteins on TRP channel function results from this second cloned TRP channel, which has initially been shown to be activated following receptor/G-protein/phospholipase C (PLC) activation [9], [10], [11], [12]. Later experiments demonstrated the activation of TRPL by polyunsaturated fatty acids, whose release results from the breakdown of
PDZ domains
The name “PDZ domain” is delineated form the protein sequences of PSD-95 (protein of postsynaptic density with 95 kDa), Discs-large (Drosophila septate junction protein), and ZO-1 (protein 1 of the zona occludens) [5]. PDZ domains are formed by about 100 amino acids from which a consensus sequence of 40 amino acids has been extracted. The PDZ domains specifically bind to C-terminal sequences ending with an X-S/T-X-hydrophobic amino acid sequence. The known PDZ-binding motifs can be divided into
Structural aspects of PDZ domains in INAD for the formation of a macromolecular complex
Proteins of the Drosophila phototransduction cascade are localized in the rhabdomer, a specialized membrane compartment of the photoreceptor cells. The identification of INAD lead to the understanding that the proteins involved in phototransduction of Drosophila melanogaster are organized in a macromolecular complex [30]. INAD is composed of five PDZ domains and tethers the cation channel (TRP), phospholipase (PLC=NORPA), and an eye-specific protein kinase C (PKC=INAC). All these proteins form
Functional aspects of INAD
Many studies have clarified the proteins and sequence domains involved in protein–protein interactions. We were recently able to demonstrate functional consequences of a protein–protein interaction and, thereby, solved an old controversy on the activation mechanism of Drosophila TRP [40]. Drosophila phototransduction depends on G-protein-initiated activation of PLC and subsequent calcium entry [41], [42], [43].
In mammalian cells, G-protein-induced activation of PLC results in a release of
Mammalian INAD homologous proteins
After the mammalian TRP homologous cation channels had successfully been cloned by database searching, this approach was also used to identify mammalian INAD homologous channels. The broad distribution of PDZ domains and the presence of PDZ-sequence signatures in many proteins, however, made it very difficult to identify PDZ proteins interacting with mammalian TRP channels. A human INAD-like protein (hINADL) of 1524 amino acids comprising five PDZ domains was cloned with this approach [62].
Acknowledgements
The cDNAs were kindly provided by Reinhard Paulsen and Armin Huber (Calliphora INAD) and Andrea Zobel (Drosophila TRP). The work was supported by the Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie.
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