Lecithin:cholesterol-acyl-transferase (LCAT) plays a major role in cholesterol metabolism as it is the only extracellular enzyme able to esterify cholesterol. LCAT activity is required for lipoprotein remodelling and, most specifically, for the growth and maturation of HDLs. In fact, genetic alterations affecting LCAT func- tionality may cause a severe reduction in plasma levels of HDL-cholesterol with important clinical consequences. Although several hypotheses were formulated, the exact molecular recognition mechanism between LCAT and HDLs is still unknown. We employed a combination of structural bioinformatics procedures to deepen the insights into the HDL-LCAT interplay that promotes LCAT activation and cholesterol esterification. We have generated a data-driven model of reconstituted HDL (rHDL) and studied the dynamics of an assembled rHDL::LCAT supramolecular complex, pinpointing the conformational changes originating from the interaction between LCAT and apolipoprotein A-I (apoA-I) that are necessary for LCAT activation. Specifically, we propose a mechanism in which the anchoring of LCAT lid to apoA- I helices allows the formation of a hydrophobic hood that expands LCAT active site and shields it from the solvent, allowing the enzyme to process large hydrophobic substrates.

rHDL modelling and the anchoring mechanism of LCAT activation / T. Laurenzi, C. Parravicini, L. Palazzolo, U. Guerrini, E. Gianazza, L. Calabresi, I. Eberini. - In: JOURNAL OF LIPID RESEARCH. - ISSN 0022-2275. - (2020). [Epub ahead of print]

rHDL modelling and the anchoring mechanism of LCAT activation

T. Laurenzi
Primo
;
C. Parravicini
Secondo
;
L. Palazzolo;U. Guerrini;E. Gianazza;L. Calabresi
Penultimo
;
I. Eberini
Ultimo
2020

Abstract

Lecithin:cholesterol-acyl-transferase (LCAT) plays a major role in cholesterol metabolism as it is the only extracellular enzyme able to esterify cholesterol. LCAT activity is required for lipoprotein remodelling and, most specifically, for the growth and maturation of HDLs. In fact, genetic alterations affecting LCAT func- tionality may cause a severe reduction in plasma levels of HDL-cholesterol with important clinical consequences. Although several hypotheses were formulated, the exact molecular recognition mechanism between LCAT and HDLs is still unknown. We employed a combination of structural bioinformatics procedures to deepen the insights into the HDL-LCAT interplay that promotes LCAT activation and cholesterol esterification. We have generated a data-driven model of reconstituted HDL (rHDL) and studied the dynamics of an assembled rHDL::LCAT supramolecular complex, pinpointing the conformational changes originating from the interaction between LCAT and apolipoprotein A-I (apoA-I) that are necessary for LCAT activation. Specifically, we propose a mechanism in which the anchoring of LCAT lid to apoA- I helices allows the formation of a hydrophobic hood that expands LCAT active site and shields it from the solvent, allowing the enzyme to process large hydrophobic substrates.
LCAT, HDL/Structure, Physical biochemistry, Cholesterol metabolism, Diseases/Dyslipidemias, Structural bioinformatics, LCAT deficiency, Molecular modellin
Settore BIO/10 - Biochimica
Settore BIO/14 - Farmacologia
2-dic-2020
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/796719
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