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J. Biol. Chem., Vol. 280, Issue 48, 40074-40083, December 2, 2005

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Role of the Lid Hydrophobicity Pattern in Pancreatic Lipase Activity^*

Annick Thomas1, Maya Allouche2, Frédéric Basyn3, Robert Brasseur4, and Brigitte Kerfelec5

From the Centre de Biophysique Moléculaire Numérique, Faculté Agronomique, 5030 Gembloux, Belgium and the Inserm U476, Inra UMR 1260, Université de la Méditerranée, Faculté demédecine, 27 Bd Jean Moulin, 13385 Marseille cedex 5, France

Pancreatic lipase is a soluble globular protein that must undergo structural modifications before it can hydrolyze oil droplets coated with bile salts. The binding of colipase and movement of the lipase lid open access to the active site. Mechanisms triggering lid mobility are unclear. The ^*KNILSQIVDIDGI^* fragment of the lid of the human pancreatic lipase is predicted by molecular modeling to be a tilted peptide. Tilted peptides are hydrophobicity motifs involved in membrane fusion and more globally in perturbations of hydrophobic/hydrophilic interfaces. Analysis of this lid fragment predicts no clear consensus of secondary structure that suggests that its structure is not strongly sequence determined and could vary with environment. Point mutations were designed to modify the hydrophobicity profile of the [240–252] fragment and their consequences on the lipase-mediated catalysis were tested. Two mutants, in which the tilted peptide motif was lost, also have poor activity on bile salt-coated oil droplets and cannot be reactivated by colipase. Conversely, one mutant in which a different tilted peptide is created retains colipase dependence. These results suggest that the tilted hydrophobicity pattern of the [240–252] fragment is neither important for colipase binding to lipase, nor for interfacial binding but is important to trigger the maximal catalytic efficiency of lipase in the presence of bile salt.

Received for publication, February 24, 2005 , and in revised form, September 7, 2005.

^* The work was supported in part by Fonds de la Recherche Scientifique Médicale Grant 3.4568.03 (Fonds National de la Recherche Scientifique (FNRS), Belgium). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Research Director Inserm (France).

² Supported by a French-Tunisian grant from the French Ministry.

³ Supported by a grant from FNRS-Télévie.

⁴ Supported by the DR FNRS (Belgium).

⁵ To whom correspondence should be addressed. Tel.: 33-491-29-41-10; Fax: 33-491-78-21-01; E-mail: Brigitte.Kerfelec{at}medecine.univ-mrs.fr.

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