Specific binding of dehydroepiandrosterone to the N terminus of the microtubule-associated protein MAP2.
The effect of neurosteroids is mediated through their membrane or nuclear receptors. However, no dehydroepiandrosterone (DHEA)-specific receptors have been evidenced so far in the brain. In this paper, we showed by isothermal titration calorimetry that the DHEA specifically binds to the dendritic brain microtubule-associated protein MAP2C with an association constant of 2.7 x 10(7) m-1 and at a molar ratio of 1:1. By partial tryptic digestions and mass spectrometry analysis, we found that the binding involved the N-terminal region of MAP2C. Interestingly, MAP2C displays homologies with 17 beta-hydroxysteroid dehydrogenase 1, an enzyme required for estrogen synthesis. Based on these sequence homologies and on the x-ray structure of the DHEA-binding pocket of 17 beta-hydroxysteroid dehydrogenase 1, we modeled the complex of DHEA with MAP2C. The binding of DHEA to MAP2C involved specific hydrogen bonds that orient the steroid into the pocket. This work suggests that DHEA can directly influence brain plasticity via MAP2C binding. It opens interesting ways for understanding the role of DHEA in the brain.
Laurine
Emmanuelle
E
Ecole Pratique des Hautes Etudes, Université Montpellier II, Place Eugène Bataillon, CC94, 34095 Montpellier cedex 05, France.
Lafitte
Daniel
D
Grégoire
Catherine
C
Sérée
Eric
E
Loret
Erwann
E
Douillard
Soazig
S
Michel
Bernard
B
Briand
Claudette
C
Verdier
Jean-Michel
JM
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000595:Amino Acid Sequence; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002151:Calorimetry; D002467:Cell Nucleus / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D003599:Cytoskeleton / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D013058:Mass Spectrometry; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014357:Trypsin / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry
D000276:Adjuvants, Immunologic; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D010455:Peptides; D020033:Protein Isoforms; D014404:Tubulin; D003687:Dehydroepiandrosterone; D004247:DNA; D014357:Trypsin