A primer on ankyrin repeat function in TRP channels and beyond

Abstract

Transient Receptor Potential (TRP) channels are rapidly gaining attention as important receptors and transducers of diverse sensory and environmental cues. Recent progress in the field has provided new insights into the structure and function of the ankyrin repeat motifs present in the Nterminal cytosolic domain of many TRP channels. The topics addressed in this review include the structural features of canonical ankyrin repeats, new clues into the functions these repeats perform in cells, and how this information can be applied to develop further experiments on TRP channels and other proteins containing ankyrin repeats.TRP proteins form a large family of ion channels particularly important in animals from worms to man, with more than 30 members in mammals. 1 The founding family member, the Drosophila trp gene -named for the "transient receptor potential" phenotype its mutation causes in light perception by photoreceptors -was first cloned in 1989. 2 The functions assigned to TRP channels in physiology are constantly expanding. They are key transducers of sensory signals, and are generally important in sensing information about the environment in both neuronal and non-neuronal cells (see ref. 3 for comprehensive reviews). Some TRP channels are found in excitable cells of the sensory nervous system, while others are expressed in various other tissues and organs. TRP channels have been implicated in many physiological processes, including calcium and magnesium homeostasis, neuronal growth, temperature sensation and pain perception, to name a few. For example, TRPV1 senses painfully hot temperatures, low extracellular pH and the capsaicin of "hot" chili peppers, while TRPA1 senses many painful chemical stimuli, including the pungent compounds in wasabi and cinnamon. TRPV1 and TRPA1 are expressed in partially overlapping sets of nociceptor neurons that transmit pain signals to the brain.At a molecular level, TRP channels assemble as tetramers through a channel domain that spans the membrane six times and has sequence similarity to voltage-gated ion channels. TRP channels also have large N-and C-terminal cytosolic domains that flank the transmembrane channel domain. These cytosolic domains participate in channel gating and regulation and sense information about the cellular state -ion and metabolite levels, for example. The TRP channel family is divided into seven subfamilies based on sequence similarity 1 : TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), TRPV (vanilloid), and TRPN (NOMPC). Several of these subfamilies -TRPA, TRPC, TRPN and TRPV -have ankyrin repeat sequence motifs in their N-terminal cytosolic domains. Recent work from my lab and others has taken a structural biology approach to elucidate the roles of these ankyrin repeats in TRP channel function. [4][5][6][7][8][9] The emerging structural and functional features of these TRP channel ankyrin repeats are the focus of this short review. NIH Public Access Ankyrin repeats and their structureAnkyrin rep...

Molecular modeling‐based evaluation of dual function of IκBζ ankyrin repeat domain in toll‐like receptor signaling

“…The 28 residues that form a long loop are located in between the helices of a1 and a2 of ANK4, which was consistent with the results of the PSIPRED secondary structure prediction (Jones and Thornton, 1996). Additionally, comparison of the modeled ANK protein (with insertion) with different ARD members did not reveal any similar insertions within the 33 amino acid long ANK repeat motif as listed in a recent review (Mosavi et al, 2004;Gaudet 2008). However, in the present study, the insertion took place within the ANK repeat.…”

Molecular Bases of Multimodal Regulation of a Fungal Transient Receptor Potential (TRP) Channel

“…On the other hand, the molecular architectures of the N and C termini of the cytosolic domains are highly diverse among the TRP family members. The domains usually consist of multiple functional domains or regions for channel regulation (16), such as ankyrin repeats as bait for protein or ligand interactions (17), a coiled-coil region that probably functions in channel assembly (18), an EF-hand motif (19) or a calmodulin binding motif (20) for Ca 2ϩ -mediated regulation, and a phosphatidylinositol phosphate (PIP) binding domain for regulation (21). The structural information for TRP channels is limited to a few individual functional modules (22)(23)(24)(25)(26)(27)(28), and low resolution electron microscopy structural studies of entire TRP channels revealed large cytosolic domains with chamber-like structures (29 -32, 77).…”

Role of the Transient Receptor Potential Vanilloid 5 (TRPV5) Protein N Terminus in Channel Activity, Tetramerization, and Trafficking

“…Ankyrin repeats are composed of multiple protein/ligand interaction domains of ϳ33 residues each with a highly conserved helix-loop-helix structure (9, 10). ATP and calmodulin have been demonstrated to bind TRP ankyrin repeats; however, more binding factors remain to be identified (10,11). Within the C terminus, a highly conserved short hydrophobic stretch, called the TRP box region, has been identified in TRPC, TRPM, and TRPV families (12).…”

“…Highly conserved ankyrin repeats are present in the N termini of TRPC, TRPV, and TRPA channels. Ankyrin repeats are composed of multiple protein/ligand interaction domains of ϳ33 residues each with a highly conserved helix-loop-helix structure (9,10). ATP and calmodulin have been demonstrated to bind TRP ankyrin repeats; however, more binding factors remain to be identified (10,11).…”