Disorder-To-Order Transition of MAGI-1 PDZ1 C-Terminal Extension upon Peptide Binding: Thermodynamic and Dynamic Insights

TY - JOUR

T1 - Disorder-To-Order Transition of MAGI-1 PDZ1 C-Terminal Extension upon Peptide Binding

T2 - Thermodynamic and Dynamic Insights

AU - Ramírez, Juan

AU - Recht, Raphaël

AU - Charbonnier, Sebastian

AU - Ennifar, Eric

AU - Atkinson, R Andrew

AU - Travé, Gilles

AU - Nominé, Yves

AU - Kieffer, Bruno

PY - 2015/2/17

Y1 - 2015/2/17

N2 - PDZ domains are highly abundant protein-protein interaction modules commonly found in multidomain scaffold proteins. The PDZ1 domain of MAGI-1, a protein present at cellular tight junctions that contains six PDZ domains, is targeted by the E6 oncoprotein of the high-risk human papilloma virus. Thermodynamic and dynamic studies using complementary isothermal titration calorimetry and nuclear magnetic resonance (NMR) (15)N heteronuclear relaxation measurements were conducted at different temperatures to decipher the molecular mechanism of this interaction. Binding of E6 peptides to the MAGI-1 PDZ1 domain is accompanied by an unusually large and negative change in heat capacity (ΔC(p)) that is attributed to a disorder-to-order transition of the C-terminal extension of the PDZ1 domain upon E6 binding. Analysis of temperature-dependent thermodynamic parameters and (15)N NMR relaxation data of a PDZ1 mutant in which this disorder-to-order transition was abolished allows the unusual thermodynamic signature of E6 binding to be correlated to local folding of the PDZ1 C-terminal extension. Comparison of the exchange contributions observed for wild-type and mutant proteins explains how variation in the solvent-exposed area may compensate for the loss of conformational entropy and further designates a distinct set of a few residues that mediate this local folding phenomena.

AB - PDZ domains are highly abundant protein-protein interaction modules commonly found in multidomain scaffold proteins. The PDZ1 domain of MAGI-1, a protein present at cellular tight junctions that contains six PDZ domains, is targeted by the E6 oncoprotein of the high-risk human papilloma virus. Thermodynamic and dynamic studies using complementary isothermal titration calorimetry and nuclear magnetic resonance (NMR) (15)N heteronuclear relaxation measurements were conducted at different temperatures to decipher the molecular mechanism of this interaction. Binding of E6 peptides to the MAGI-1 PDZ1 domain is accompanied by an unusually large and negative change in heat capacity (ΔC(p)) that is attributed to a disorder-to-order transition of the C-terminal extension of the PDZ1 domain upon E6 binding. Analysis of temperature-dependent thermodynamic parameters and (15)N NMR relaxation data of a PDZ1 mutant in which this disorder-to-order transition was abolished allows the unusual thermodynamic signature of E6 binding to be correlated to local folding of the PDZ1 C-terminal extension. Comparison of the exchange contributions observed for wild-type and mutant proteins explains how variation in the solvent-exposed area may compensate for the loss of conformational entropy and further designates a distinct set of a few residues that mediate this local folding phenomena.

KW - Amino Acid Sequence

KW - Magnetic Resonance Spectroscopy

KW - Molecular Sequence Data

KW - PDZ Domains

KW - Peptides

KW - Protein Conformation

KW - Thermodynamics

KW - Tight Junctions

U2 - 10.1021/bi500845j

DO - 10.1021/bi500845j

M3 - Article

C2 - 25590897

SN - 0006-2960

VL - 54

SP - 1327

EP - 1337

JO - Biochemistry

JF - Biochemistry

IS - 6

ER -