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Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST.

Publication ,  Journal Article
Hwang, S; Schmitt, AA; Luteran, AE; Toone, EJ; McCafferty, DG
Published in: Biochemistry
February 2011

Flavin-dependent histone demethylases catalyze the posttranslational oxidative demethylation of mono- and dimethylated lysine residues, producing formaldehyde and hydrogen peroxide in addition to the corresponding demethylated protein. In vivo, histone demethylase LSD1 (KDM1; BCH110) is a component of the multiprotein complex that includes histone deacetylases (HDAC 1 and 2) and the scaffolding protein CoREST. Although little is known about the affinities of or the structural basis for the interaction between CoREST and HDACs, the structure of CoREST(286-482) bound to an α-helical coiled-coil tower domain within LSD1 has recently been reported. Given the significance of CoREST in directing demethylation to specific nucleosomal substrates, insight into the molecular basis of the interaction between CoREST and LSD1 may suggest a new means of inhibiting LSD1 activity by misdirecting the enzyme away from nucleosomal substrates. Toward this end, isothermal titration calorimetry studies were conducted to determine the affinity and thermodynamic parameters characterizing the binding interaction between LSD1 and CoREST(286-482). The proteins tightly interact in a 1:1 stoichiometry with a dissociation constant (K(d)) of 15.9 ± 2.07 nM, and their binding interaction is characterized by a favorable enthalpic contribution near room temperature with a smaller entropic penalty at pH 7.4. Additionally, one proton is transferred from the buffer to the heterodimeric complex at pH 7.4. From the temperature dependence of the enthalpy change of interaction, a constant-pressure heat capacity change (ΔC(p)) of the interaction was determined to be -0.80 ± 0.01 kcal mol(-1) K(-1). Notably, structure-driven truncation of CoREST revealed that the central binding determinant lies within the segment of residues 293-380, also known as the CoREST "linker" region, which is a central isolated helix that interacts with the LSD1 coiled-coil tower domain to create a triple-helical bundle. Thermodynamic parameters obtained from the binding between LSD1 and the linker region of CoREST are similar to those obtained from the interaction between LSD1 and CoREST(286-482). These results provide a framework for understanding the molecular basis of protein-protein interactions that govern nucleosomal demethylation.

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Published In

Biochemistry

DOI

EISSN

1520-4995

ISSN

0006-2960

Publication Date

February 2011

Volume

50

Issue

4

Start / End Page

546 / 557

Related Subject Headings

  • Thermodynamics
  • Surface Plasmon Resonance
  • Substrate Specificity
  • Repressor Proteins
  • Recombinant Proteins
  • Protein Structure, Tertiary
  • Protein Interaction Mapping
  • Protein Binding
  • Nucleosomes
  • Nerve Tissue Proteins
 

Citation

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Hwang, S., Schmitt, A. A., Luteran, A. E., Toone, E. J., & McCafferty, D. G. (2011). Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST. Biochemistry, 50(4), 546–557. https://doi.org/10.1021/bi101776t
Hwang, Sunhee, Allison A. Schmitt, Andrea E. Luteran, Eric J. Toone, and Dewey G. McCafferty. “Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST.Biochemistry 50, no. 4 (February 2011): 546–57. https://doi.org/10.1021/bi101776t.
Hwang S, Schmitt AA, Luteran AE, Toone EJ, McCafferty DG. Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST. Biochemistry. 2011 Feb;50(4):546–57.
Hwang, Sunhee, et al. “Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST.Biochemistry, vol. 50, no. 4, Feb. 2011, pp. 546–57. Epmc, doi:10.1021/bi101776t.
Hwang S, Schmitt AA, Luteran AE, Toone EJ, McCafferty DG. Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST. Biochemistry. 2011 Feb;50(4):546–557.
Journal cover image

Published In

Biochemistry

DOI

EISSN

1520-4995

ISSN

0006-2960

Publication Date

February 2011

Volume

50

Issue

4

Start / End Page

546 / 557

Related Subject Headings

  • Thermodynamics
  • Surface Plasmon Resonance
  • Substrate Specificity
  • Repressor Proteins
  • Recombinant Proteins
  • Protein Structure, Tertiary
  • Protein Interaction Mapping
  • Protein Binding
  • Nucleosomes
  • Nerve Tissue Proteins