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J. Biol. Chem., Vol. 280, Issue 3, 1953-1961, January 21, 2005

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Human Polyserase-2, a Novel Enzyme with Three Tandem Serine Protease Domains in a Single Polypeptide Chain^*

Santiago Cal, Víctor Quesada, María Llamazares, Araceli Díaz-Perales, Cecilia Garabaya, and Carlos López-Otín

From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain

We have cloned a human cDNA encoding a new serine protease that has been called polyserase-2 (polyserine protease-2) because it is the second identified human enzyme with several tandem serine protease domains in its amino acid sequence. The first serine protease domain contains all characteristic features of these enzymes, whereas the second and third domains lack one residue of the catalytic triad of serine proteases and are predicted to be catalytically inactive. This complex domain organization is also present in the sequences of mouse and rat polyserase-2 and resembles that of polyserase-1, which also contains three serine protease domains in its amino acid sequence. However, polyserase-2 lacks additional domains present in polyserase-1, including a type II transmembrane motif and a low-density lipoprotein receptor A module. Enzymatic analysis demonstrated that both full-length polyserase-2 and its first serine protease domain hydrolyzed synthetic peptides used for assaying serine proteases. Nevertheless, the activity of the isolated domain was greater than that of the entire protein, suggesting that the two catalytically inactive serine protease domains of polyserase-2 may modulate the activity of the first domain. Northern blot analysis showed that polyserase-2 is expressed in fetal kidney; adult skeletal muscle, liver, placenta, prostate, and heart; and tumor cell lines derived from lung and colon adenocarcinomas. Finally, analysis of post-translational processing mechanisms of polyserase-2 revealed that, contrary to those affecting to the membrane-bound polyserase-1, this novel polyprotein is a secreted enzyme whose three protease domains remain as an integral part of a single polypeptide chain.

Received for publication, August 10, 2004 , and in revised form, October 29, 2004.

^* This work was supported by grants from the Comisión Interministerial de Ciencia y Tecnología-Spain, Gobierno del Principado de Asturias, Fundación la Caixa, and European Union (FP5, Cancer Degradome-FP6). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias and Red de Centros de Cancer-Instituto Carlos III, Spain. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ627034, AJ784938, and AJ784939.

To whom correspondence should be addressed. Tel.: 34-985-106282; Fax: 34-985-103564; E-mail: santical{at}uniovi.es.

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