How Do TrkA and p75 Interact?

Abstract

Nerve growth factor (NGF) binds to two structurally unrelated cell surface receptors, the p75 neurotrophin receptor (p75) and the receptor tyrosine kinase TrkA. p75 increases TrkA’s responsiveness to NGF, and coexpression of the two receptors appears to lead to the formation of binding sites with higher affinity for NGF than that of either receptor alone. This suggests that the high-affinity NGF-binding site may involve a complex containing both p75 and TrkA. Wehrmann et al . determined the crystal structure of the complete TrkA extracellular domain in complex with NGF and found that this structure was not incompatible with the existence of a 1:2:1 TrkA-NGF-p75 ternary complex. To investigate this possibility in a cellular context, the authors determined interactions between proteins (p75 and a truncated form of TrkA) fused to fragments of β-galactosidase (which become functional when brought together) that were expressed in C2C12 myoblasts. NGF promoted formation of TrkA homodimers but not that of TrkA-p75 heterodimers (which also did not exist in untreated cells); p75 formed oligomers in the absence of ligand, and NGF did not affect this oligomerization. When corrected for background binding, Scatchard analysis of 125 I-NGF binding in both PC12 cells and C2C12 cells expressing TrkA and p75 constructs failed to reveal the higher-affinity NGF binding site. Thus, the authors conclude that functional interactions between p75 and TrkA likely depend on downstream signaling rather than physical complexes involving the two receptors. In discussing this research, Barker suggests that p75 could pass NGF to TrkA in a ternary complex that exists too briefly to be detected by the β-galactosidase complementation assay. T. Wehrman, X. He, B. Raab, A. Dukipatti, H. Blau, K. C. Garcia, Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors. Neuron 53 , 25-38 (2007). [PubMed] P. A. Barker, High affinity not in the vicinity? Neuron 53 , 1-4 (2007). [PubMed]