{'fraction_non_alphanumeric': 0.017107309486780714, 'fraction_numerical': 0.0007776049766718507, 'mean_word_length': 5.956756756756757, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Coaction of Electrostatic and Hydrophobic Interactions: Dynamic Constraints on Disordered TrkA Juxtamembrane Domain.

In the receptor tyrosine kinase family, conformational change induced by ligand binding is transmitted across membrane via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Membrane dynamics makes it challenging to study the structural mechanism of receptor activation in experiments. In this study, we employed all-atom molecular dynamics with Highly Mobile Membrane-Mimetic to capture the native conformation of the JMD in tropomyosin receptor kinase A (TrkA). We found that PIP2 lipids engage in stable binding to multiple basic residues and competes with salt bridges within the peptide. We discovered hydrophobic insertion into the membrane and perturb it through computationally-designed point mutations. Vesicle-binding experiment indicates that the contribution from hydrophobic insertion is comparable to electrostatic binding. Immunoblot experiment shows that enhanced TrkA-JMD insertion promotes receptor ubiquitination. Our joint work points to a scenario where basic and hydrophobic residues on disorder domains respectively interact with lipid headgroups and tails, to restrain flexibility and potentially modulate protein function.