Cholesterol-recognition motifs in the transmembrane domain of the tyrosine kinase receptor family: The case of TRKB

Cholesterol is an essential constituent of cell membranes. The discovery of cholesterol-recognition amino acid consensus (CRAC) motif in proteins indicated a putative direct, non-covalent interaction between cholesterol and proteins. In the present study, we evaluated the presence of a CRAC motif and its inverted version (CARC) in the transmembrane region (TMR) of the tyrosine kinase receptor family (RTK) in several species using in silico methods. CRAC motifs were found across all species analyzed, while CARC was found only in vertebrates. The tropomyosin-related kinase B (TRKB), a member of the RTK family, through interaction with its endogenous ligand brain-derived neurotrophic factor (BDNF) is a core participant in the neuronal plasticity process and exhibits a CARC motif in its TMR. Upon identifying the conserved CARC motif in the TRKB, we performed molecular dynamics simulations of the mouse TRKB.TMR. The simulations indicated that cholesterol interaction with the TRKB CARC motif occurs mainly at the central Y433 residue. Our binding assay suggested a bell-shaped effect of cholesterol on BDNF interaction with TRKB receptors, and our results suggest that CARC/CRAC motifs may play a role in the function of the RTK family TMR.

Automated summary

The study identified the presence of cholesterol-recognition amino acid consensus (CRAC) and its inverted version (CARC) in different species, with CARC only found in vertebrates. TRKB, a member of the RTK family, may play a crucial role in neuronal plasticity and exhibits a CARC motif in its transmembrane region. Molecular dynamics simulations showed that cholesterol interaction with the TRKB CARC motif mainly occurs at the central Y433 residue. The study suggests that CARC/CRAC motifs may be involved in the function of the RTK family transmembrane region.