Homo sapiens TrkA Receptor

Natalie Stone '25 and Brooke Avila '27

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I. Introduction

TrkA receptor is a type of tropomyosin receptor kinase that neurotrophins bind to inducing downstream signaling. Other types of tropomyosin receptor kinases include TrkB and TrkC that have different downstream signaling and bind different ligands to function. Neurotrophins are a group of proteins that play a role in neuron survival, development and function and thus are found in the peripheral nervous system and in neurons. This pathway plays a big role in pain. Neurotrophins include nerve growth factors which bind to TrkA receptors and brain-derived nerve growth factors that bind to TrkC and TrkB receptors. Neurotrophin-7 and neurotrophin-6 are also ligands for the TrkA receptor. Like other tyrosine kinase receptors, TrkA is activated by dimerization which results in intracellular autophosphorylation and signal transduction cascade. TrkA receptor binding results in downstream signaling that includes the regulation of the synthesis of transcription factors, apoptosis, cell growth, exocytosis and secretion

II. General Structure

The TrkA receptor is produced as a single peptide chain and one domain spanning the membrane. TrkA contains 5 helices and 22 TrkA consists a transmembrane region and intracellular kinase domain region. The ECD (extracellular domain) of the TrkA is a dimer and has a twisted, almost helical shape due to the way the parts rotate and connect . The TrkA receptor has a N-terminal and C-terminal. TrkA also contains five extracellular domains referred to as D1, D2, D3, D4 or Ig-C1 (immunoglobulin-like-C1 type domain), and D5 or Ig-C2 .

D1 D2 and D3 are leucine-rich repeat domains .D1, D2, and D3 all have a superhelical topology and are joined as one structural domain. D2 is the "body" of the structure . In order to protect D2, D1 and D3 contain cap structures known as the N-terminal cap and the C-terminal cap . D1 and D3 are the . The cysteine residues are important for forming disulfide bonds to help stabilize the receptor.


Figure 1. Displays a simplistic version of the main components of the TrkA receptor. TrkA contains two cysteine-rich domains (Domain 1 and Domain 3). The leucine-rich repeat is referring to Domain 2. TrkA contains two IgG-like domains which include Domain 4 and Domain 5. All of these domains are extracellular and a ligand binds to Domain 5 to activate downstream signaling.

III. Ligand Binding

Domains 4 and 5 are known as the immunoglobulin rich domains. NFGs primarily bind to the D5 domain, making this region, along with the intracellular kinase domain, a common target for inhibitors of the TrkA receptor. D4 or Ig-1 is composed of and is stablilized by .

D4 is connected to LRR via a . This interaction is reinforced by a salt bridge, hydrophobic clusters, and van der Waals interactions . D5 consists of a β-sandwich which is formed by two four stranded sheets and ultimately creates the immunoglobulin structural motif. The first stranded sheets are known as . The second stranded sheets are known as . D4 and D5 are connected through van der Waals and hydrophobic interactions involving the EF-loop of D4 and the BC and DE-loops of D5.

IV. Receptor Binding

When an NFG binds to the D5 domain of the TrkA receptor, the sides of the homodimer are engaged by the C-terminal of the D5 domain The immunoglobulin structural motifs of domain 5 are important for the protein-protein interaction with the nerve growth facter. The TrkA-NGF complex is symmetrical with two halves of the TrkA mirrored across the NGFs central axis. An analogy of a crab and pinchers is used to describe the receptor binding; the crab is the ligand (NGF) and the pinchers are the D1-D5 fomains of the TrkA receptor. There is no conformational change when NGF binds to TrkA. The match between the specificity patch on domain 5 of TrkA and the NFG is what determines if the NFG can bind to TrkA and activate it. D5 and NGF binding results in the top loops of the D5 domain penetrating a saddle-like depression along the tips of the NGF central . The residue at the tip of the AB loop is in imtimate contact with the NGF . Thr340, Asn356, and Asn365 play critical roles in providing structural stablilization during the interaction of NGF with the D5 domain of TrkA .

Residues 340-382 have direct interactions with NGF during binding . The NGF engages the D5 domain of TrkA through two specificity patches and two common patches. The common patches are formed by the β-sheet of NGF , which stacks against the phenyl group of Phe327, facilitating a hydrogen bond with the carbonyl oxygen of Asn349 . In contrast, the specificity patches are made up of the N-terminal residues of NGF that pack against the ABED sheet of D5 .

His4 and Ile6 are key receptor-binding determinants. Ile6 interacts with a hydrophobic pocket on D5, which is structurally adapted to accoommodate ligand binding to TrkA. The base of the hydrophobic pocket is formed by a disulfide bridge (between the side chains of Val294 and Leu333) , while the pocket walls are composed of side chains of Val294, Met296, Pro302, and Leu33 . Additionally, His4 interacts with Ser304 through, and Glu11 , also, forms hydrogen bonds with Arg347 . Both interactions play a crucial role in stabilizing the binding on D5 .


VI. References

Barker, P. A., and Shooter, E. M. (1995). The interaction between the two receptors for NGF, p75lntr and Trka.Life and Death in the Nervous System 71–85. https://doi.org/10.1016/b978-0-08-042527-6.50011-0

Bertrand, T., Kothe, M., Liu, J., Dupuy, A., Rak, A., Berne, P. F., Davis, S., Gladysheva, T., Valtre, C., Crenne, J. Y., & Mathieu, M. (2012). The crystal structures of trka and trkb suggest key regions for achieving selective inhibition. Journal of Molecular Biology, 423(3), 439–453. https://doi.org/10.1016/j.jmb.2012.08.002

Eggert, A., Ikegaki, N., Liu, X., Chou, T. T., Lee, V. M., Trojanowski, J. Q., & Brodeur, G. M. (2000). Molecular dissection of trka signal transduction pathways mediating differentiation in human neuroblastoma cells.Oncogene 19(16), 2043–2051.

Franco, M. L., Nadezhdin, K. D., Goncharuk, S. A., Mineev, K. S., Arseniev, A. S., & Vilar, M. (2020). Structural basis of the transmembrane domain dimerization and rotation in the activation mechanism of the TRKA receptor by nerve growth factor. Journal of Biological Chemistry, 295 (1), 275–286. https://doi.org/10.1074/jbc.ra119.011312

Urfer, R., Tsoulfas, P., O’Connell, L., Hongo, J.-A., Zhao, W., & Presta, L. G. (1998). High resolution mapping of the binding site of trka for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors.Journal of Biological Chemistry, 273 (10), 5829–5840. https://doi.org/10.1074/jbc.273.10.5829

Wehrman, T., He, X., Raab, B., Dukipatti, A., Blau, H., & Garcia, K. C. (2007). Structural and mechanistic insights into nerve growth factor interactions with the TrkA and P75 receptors. Neuron, 53(1), 25–38. https://doi.org/10.1016/j.neuron.2006.09.034

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