DOPA decarboxylase, the dimeric enzyme responsible for the synthesis of neurotransmitters dopamine and serotonin, is involved in severe neurological diseases such as Parkinson disease, schizophrenia, and depression. Binding of the pyridoxal-5'-phosphate (PLP) cofactor to the apoenzyme is thought to represent a central mechanism for the regulation of its activity. We solved the structure of the human apoenzyme and found it exists in an unexpected open conformation: compared to the pig kidney holoenzyme, the dimer sub-units move 20 angstrom apart and the two active sites become solvent exposed. Moreover, by tuning the PLP concentration in the crystals, we obtained two more structures with different conformations of the active site. Analysis of three-dimensional data coupled to a kinetic study allows to identify the structural determinants of the open/close conformational change occurring upon PLP binding and thereby propose a model for the preferential degradation of the apoenzymes of Group II decarboxylases.

Open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to Group II decarboxylases / Giardina, Giorgio; R., Montioli; Gianni, Stefano; B., Cellini; Paiardini, Alessandro; C., Borri Voltattorni; Cutruzzola', Francesca. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 108:51(2011), pp. 20514-20519. [10.1073/pnas.1111456108]

Open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to Group II decarboxylases

GIARDINA, Giorgio;GIANNI, STEFANO;PAIARDINI, ALESSANDRO;CUTRUZZOLA', Francesca
2011

Abstract

DOPA decarboxylase, the dimeric enzyme responsible for the synthesis of neurotransmitters dopamine and serotonin, is involved in severe neurological diseases such as Parkinson disease, schizophrenia, and depression. Binding of the pyridoxal-5'-phosphate (PLP) cofactor to the apoenzyme is thought to represent a central mechanism for the regulation of its activity. We solved the structure of the human apoenzyme and found it exists in an unexpected open conformation: compared to the pig kidney holoenzyme, the dimer sub-units move 20 angstrom apart and the two active sites become solvent exposed. Moreover, by tuning the PLP concentration in the crystals, we obtained two more structures with different conformations of the active site. Analysis of three-dimensional data coupled to a kinetic study allows to identify the structural determinants of the open/close conformational change occurring upon PLP binding and thereby propose a model for the preferential degradation of the apoenzymes of Group II decarboxylases.
2011
apoprotein; fret; kinetics; shiff base; stability
01 Pubblicazione su rivista::01a Articolo in rivista
Open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to Group II decarboxylases / Giardina, Giorgio; R., Montioli; Gianni, Stefano; B., Cellini; Paiardini, Alessandro; C., Borri Voltattorni; Cutruzzola', Francesca. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 108:51(2011), pp. 20514-20519. [10.1073/pnas.1111456108]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/426205
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