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Cholesterol‐recognition motifs in the transmembrane domain of the tyrosine kinase receptor family: The case of TRKB
Author(s) -
Cannarozzo Cecilia,
Fred Senem Merve,
Girych Mykhailo,
Biojone Caroline,
Enkavi Giray,
Róg Tomasz,
Vattulainen Ilpo,
Casarotto Plinio C,
Castrén Eero
Publication year - 2021
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.15218
Subject(s) - tropomyosin receptor kinase b , transmembrane domain , transmembrane protein , receptor tyrosine kinase , brain derived neurotrophic factor , microbiology and biotechnology , tyrosine kinase , tyrosine , biology , receptor , chemistry , neurotrophic factors , biochemistry
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.