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J. Biol. Chem., Vol. 280, Issue 22, 21272-21283, June 3, 2005

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The Kell Protein of the Common K2 Phenotype Is a Catalytically Active Metalloprotease, whereas the Rare Kell K1 Antigen Is Inactive

IDENTIFICATION OF NOVEL SUBSTRATES FOR THE KELL PROTEIN^*

Audrey Clapéron, Christiane Rose, Pierre Gane¶, Emmanuel Collec¶, Olivier Bertrand¶, and Tanja Ouimet||

From the INSERM U573, 75014 Paris, France and ^¶INSERM Unites Mixtes de Recherche et de Services 665 Groupement d'Interêt Public Institut National de Transfusion Sanguine, 75015 Paris, France

The Kell blood group is a highly polymorphic system containing over 20 different antigens borne by the protein Kell, a 93-kDa type II glycoprotein that displays high sequence homology with members of the M13 family of zinc-dependent metalloproteases whose prototypical member is neprilysin. Kell K1 is an antigen expressed in 9% of the Caucasian population, characterized by a point mutation (T193M) of the Kell K2 antigen, and located within a putative N-glycosylation consensus sequence. Recently, a recombinant, non-physiological, soluble form of Kell was shown to cleave Big ET-3 to produce the mature vasoconstrictive peptide. To better characterize the enzymatic activity of the Kell protein and the possible differences introduced by antigenic point mutations affecting post-translational processing, the membrane-bound forms of the Kell K1 and Kell K2 antigens were expressed either in K562 cells, an erythroid cell line, or in HEK293 cells, a non-erythroid system, and their pharmacological profiles and enzymatic specificities toward synthetic and natural peptides were evaluated. Results presented herein reveal that the two antigens possess considerable differences in their enzymatic activities, although not in their trafficking pattern. Indeed, although both antigens are expressed at the cell surface, Kell K1 protein is shown to be inactive, whereas the Kell K2 antigen binds neprilysin inhibitory compounds such as phosphoramidon and thiorphan with high affinity, cleaves the precursors of the endothelin peptides, and inactivates members of the tachykinin family with enzymatic properties resembling those of other members of the M13 family of metalloproteases to which it belongs.

Received for publication, January 4, 2005 , and in revised form, March 2, 2005.

^* 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.

A Fondation pour la Recherche Medicale fellow.

^|| To whom correspondence should be addressed: INSERM U573, Centre Paul Broca, 2ter rue d'Alésia, 75014 Paris, France. Tel.: 33-1-40-78-92-80; Fax: 33-1-45-80-72-93; E-mail: ouimet{at}broca.inserm.fr.

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This article has been cited by other articles:

				Q. Sha, C. M. Redman, and S. Lee Endothelin-3-converting Enzyme Activity of the KEL1 and KEL6 Phenotypes of the Kell Blood Group System J. Biol. Chem., March 17, 2006; 281(11): 7180 - 7182. [Abstract] [Full Text] [PDF]