TY - JOUR
T1 - Cholesterol-recognition motifs in the transmembrane domain of the tyrosine kinase receptor family
T2 - The case of TRKB
AU - Cannarozzo, Cecilia
AU - Fred, Senem Merve
AU - Girych, Mykhailo
AU - Biojone, Caroline
AU - Enkavi, Giray
AU - Róg, Tomasz
AU - Vattulainen, Ilpo
AU - Casarotto, Plinio C.
AU - Castrén, Eero
N1 - Funding Information:
The authors thank Sulo Kolehmainen and Seija Lågas for their technical assistance. This study was funded by grants from European Research Council (#322742), EU Joint Programme ‐ Neurodegenerative Disease Research (JPND) CircProt (#301225 and #643417), Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, and the Academy of Finland (#294710, #327192 and #307416). None of the funders had a role in the data acquisition, analysis, or manuscript preparation.
Publisher Copyright:
© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - BDNF
KW - cholesterol-recognition motif
KW - TRKB
KW - tyrosine kinase family
U2 - 10.1111/ejn.15218
DO - 10.1111/ejn.15218
M3 - Article
C2 - 33825223
AN - SCOPUS:85104548790
SN - 0953-816X
VL - 53
SP - 3311
EP - 3322
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 10
ER -