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J. Biol. Chem., Vol. 279, Issue 20, 21431-21438, May 14, 2004

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Transthyretin, a New Cryptic Protease^*

Márcia Almeida Liz¶, Carlos José Faro||, Maria João Saraiva, and Mónica Mendes Sousa**

From the Molecular Neurobiology, Instituto de Biologia Molecular e Celular, 4150-180 Porto, Portugal, the ^||Centro de Neurociências de Coimbra, 3004-517 Coimbra, Portugal, and the Instituto de Ciências Biomêdicas Abel Salazar (ICBAS), Universidade do Porto, 4099-003 Porto, Portugal

Transthyretin (TTR) is a plasma homotetrameric protein that acts physiologically as a transporter of thyroxine (T₄) and retinol, in the latter case through binding to retinol-binding protein (RBP). A fraction of plasma TTR is carried in high density lipoproteins by binding to apolipoprotein AI (apoA-I). We further investigated the nature of the TTR-apoA-I interaction and found that TTR from different sources (recombinant and plasmatic) is able to process proteolytically apoA-I, cleaving its C terminus after Phe-225. TTR-mediated proteolysis was inhibited by serine protease inhibitors (phenylmethanesulfonyl fluoride, Pefabloc, diisopropyl fluorophosphate, chymostatin, and N-p-tosyl-L-phenylala-nine-chloromethyl ketone), suggesting a chymotrypsin-like activity. A fluorogenic substrate corresponding to an apoA-I fragment encompassing amino acid residues 223-228 (Abz-ESFKVS-EDDnp) was used to characterize the catalytic activity of TTR, including optimum reaction conditions (37 °C and pH 6.8) and catalytic constant (K_m = 29 µM); when complexed with RBP, TTR activity was lost, whereas when complexed with T₄, only a slight decrease was observed. Cell lines expressing TTR were able to degrade Abz-ESFKVS-EDDnp 2-fold more efficiently than control cells lacking TTR expression; this effect was reversed by the presence of RBP in cell culture media, therefore proving a TTR-specific proteolytic activity. TTR can act as a novel plasma cryptic protease and might have a new, potentially important role under physiological and/or pathological conditions.

Received for publication, February 27, 2004 , and in revised form, March 17, 2004.

^* This project was supported by Fundação para a Ciência e Tecnologia (FCT) of Portugal. 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.

^¶ Recipient of a fellowship (PRAXIS XXI/38247/BCI/2001) from Fundação para a Ciência e Tecnologia of Portugal.

^** To whom correspondence should be addressed: Molecular Neurobiology Group, Inst. de Biologia Molecular e Celular, Rua Campo Alegre 823, 4150-180 Porto, Portugal. Tel.: 351-22-6074900; Fax: 351-22-6099157; E-mail: msousa{at}ibmc.up.pt.

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