INSIBIO   05451
INSTITUTO SUPERIOR DE INVESTIGACIONES BIOLOGICAS
Unidad Ejecutora - UE
artículos
Título:
The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
Autor/es:
ARIEL A. PETRUK; MARÍA SOLEDAD LABANDA; ROSA M. S. ALVAREZ; MARCELO A. MARTÍ
Revista:
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Editorial:
ELSEVIER SCIENCE BV
Referencias:
Lugar: Amsterdam; Año: 2013 vol. 1830 p. 3570 - 3577
ISSN:
0304-4165
Resumen:
Background
Thyroxine-binding
globulin (TBG) is a non-inhibitory member of the serpin family of
proteins whose main structural element is the reactive center loop
(RCL), that, upon cleavage by proteases, is inserted into the protein
core adopting a β-strand conformation (stressed to relaxed transition,
S-to-R). After S-to-R transition thyroxine (T4) affinity decreases.
However, crystallographic studies in the presence or absence of the
hormone in different states are unable to show significant differences
in the structure and interactions of the binding site. Experimental
results also suggest the existence of several S states (differing in the
number of inserted RCL residues), associated with a differential
affinity.
Methods:
To shed light
into the molecular basis that regulates T4 affinity according to the
degree of RCL insertion in TBG, we performed extended molecular dynamics
simulations combined with several thermodynamic analysis of the T4
binding to TBG in three different S states, and in the R state.
Results
Our
results show that, despite T4 binding in the protein by similar
interactions in all states, a good correlation between the degree of RCL
insertion and the binding affinity, driven by a change in TBG
conformational entropy, was observed.
Conclusion
TBG
allosteric regulation is entropy driven. The presence of multiple S
states may allow more efficient T4 release due to protease activity.
General significance
The
presented results are clear examples of how computer simulation methods
can reveal the thermodynamic basis of allosteric effects, and provide a
general framework for understanding serpin allosteric affinity
regulation.