PICOT: A Trx- and Grx-Like Protein in Search of a Function Academic Article uri icon

abstract

  • The PKC-interacting cousin of thioredoxin (PICOT) protein was discovered based on its ability to bind PKC in human T lymphocytes. Overexpression of PICOT was found to impose negative regulatory ef- fects on PKC-dependent functions. This included the inhibition of PKC-dependent activation of c-Jun N- terminal kinase (JNK) and the activator protein 1 (AP-1) and nuclear factor kappa B (NF-B) 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 ca- nonical 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 un- clear. PICOT is involved in the regulation of heart muscle function. Its overexpression in the heart of trans- genic mice increased the ventricular function and cardiomyocyte contractility, and inhibited the overall car- diac 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 bind- ing of the latter protein to the Ca 2+ -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 NF- AT regulated genes. Whether the effects of PICOT are dependent on PKC, and whether it can mediate cata- lytic activity and/or operate as an adaptor protein are only few of the open questions related to the biological mechanism of action of PICOT.

publication date

  • January 1, 2008