PICOT: A Trx- and Grx-Like Protein in Search of a Function

The PKC-interacting cousin of thioredoxin (PICOT) protein was discovered based on its ability to bind PKCθ in human T lymphocytes. Overexpression of PICOT was found to impose negative regulatory effects on PKCθ-dependent functions. This included the inhibition of PKCθ-dependent activation of c-Jun Nterminal kinase (JNK) and the activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) transcription factors. PICOT is a modular protein consisting of a single thioredoxin (Trx)-like homology domain (HD) and two highly homologous PICOT-HDs. The overall structure of each of the three domains resembles the canonical thioredoxin fold, which is common in enzymes that catalyze disulfide bond formation. Nevertheless, the three PICOT domains lack essential catalytic cysteine residues and their mode of activity is therefore unclear. PICOT is involved in the regulation of heart muscle function. Its overexpression in the heart of transgenic mice increased the ventricular function and cardiomyocyte contractility, and inhibited the overall cardiac hypertrophy induced by pressure overload. The effects of PICOT on the cardiac tissue are likely to be mediated via the muscle LIM protein (MLP), which was shown to interact with PICOT in cardiomyocytes, and colocalize with PICOT at the Z-disc of the sarcomer. PICOT interaction with MLP interfered with binding of the latter protein to the Ca2+-dependent Ser/Thr phosphatase, calcineurin, causing the displacement of calcineurin from the Z-disc. As a result, PICOT inhibited the calcineurin-mediated dephosphorylation and nuclear translocation of nuclear factor of activated T cells (NF-AT), and the transcriptional activation of NFAT regulated genes. Whether the effects of PICOT are dependent on PKC, and whether it can mediate catalytic activity and/or operate as an adaptor protein are only few of the open questions related to the biological mechanism of action of PICOT.