Proline isomerization is a ubiquitous process that plays a key role in the folding of proteins and in the regulation of their functions. Different families of enzymes, known as "peptidyl-prolyl isomerases" (PPIases), catalyze this reaction, which involves the interconversion between the cis and trans isomers of the N-terminal amide bond of the amino acid proline. However, complete descriptions of the mechanisms by which these enzymes function have remained elusive. We show here that cyclophilin A, one of the most common PPIases, provides a catalytic environment that acts on the substrate through an electrostatic handle mechanism. In this mechanism, the electrostatic field in the catalytic site turns the electric dipole associated with the carbonyl group of the amino acid preceding the proline in the substrate, thus causing the rotation of the peptide bond between the two residues. We identified this mechanism using a combination of NMR measurements, molecular dynamics simulations, and density functional theory calculations to simultaneously determine the cis-bound and trans-bound conformations of cyclophilin A and its substrate as the enzymatic reaction takes place. We anticipate that this approach will be helpful in elucidating whether the electrostatic handle mechanism that we describe here is common to other PPIases and, more generally, in characterizing other enzymatic processes.
Cyclophilin a catalyzes proline isomerization by an electrostatic handle mechanism / C. Camilloni, A.B. Sahakyan, M.J. Holliday, N.G. Isern, F. Zhang, E.Z. Eisenmesser, M. Vendruscolo. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 111:28(2014), pp. 10203-10208.
|Titolo:||Cyclophilin a catalyzes proline isomerization by an electrostatic handle mechanism|
CAMILLONI, CARLO (Primo)
|Parole Chiave:||Enzyme catalysis; NMR spectroscopy; Catalysis; Cyclophilin A; Humans; Nuclear Magnetic Resonance, Biomolecular; Proline; Static Electricity; Molecular Dynamics Simulation; Multidisciplinary|
|Settore Scientifico Disciplinare:||Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)|
|Data di pubblicazione:||2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1073/pnas.1404220111|
|Appare nelle tipologie:||01 - Articolo su periodico|