A TPR Motif Cofactor Contributes to p300 Activity in the p53 Response

Abstract

The transcription of p53 target genes involves p300/CBP coactivators, which are multiprotein complexes that interact with the p53 activation domain. We report a cofactor in the p300 coactivator complex, Strap, which has an unusual structure, being composed almost entirely of a tandem series of six tetratricopeptide repeat (TPR) motifs. The TPR motif functions as a protein interaction domain, and it is consistent with this property that Strap harbors distinct and dedicated domains that allow it to bind and augment the interaction between different components of the p300 complex. Strap facilitates p53 activity in response to stress, in part through the stress-responsive accumulation of Strap protein and interfering with the MDM2-dependent downregulation of p53.

p53-family proteins and their regulators: hubs and spokes in tumor suppression

“…One interesting example is JMY (junction-mediating and regulatory protein), a cytoplasmic actin-binding protein that can promote microfilament polymerization and directly interacts with p53 and p300/CBP. [84][85][86][87] After DNA damage, JMY accumulates in the nucleus, in which it associates with p53 and the tetratricopeptide repeat-containing protein STRAP to form a complex that includes p300/CBP, and promotes p53-dependent transcription and apoptosis. 84,87 Interestingly, STRAP can also recruit within this complex the arginine methylase PRMT5 that modifies three residues in the C-terminal region of p53.…”

“…[84][85][86][87] After DNA damage, JMY accumulates in the nucleus, in which it associates with p53 and the tetratricopeptide repeat-containing protein STRAP to form a complex that includes p300/CBP, and promotes p53-dependent transcription and apoptosis. 84,87 Interestingly, STRAP can also recruit within this complex the arginine methylase PRMT5 that modifies three residues in the C-terminal region of p53. 88 Modification of p53 by the JMY-STRAP-PRMT5-p300/CBP complex stimulates transactivation of the p21Waf1 promoter, shifting the p53 response toward cell-cycle arrest rather than apoptosis.…”

Cofactor Strap regulates oxidative phosphorylation and mitochondrial p53 activity through ATP synthase

“…At the later stages of damage, both Strap and p53 take on a more nuclear localisation (Figure 4e) where Strap can function as a nuclear p53 co-factor. [9][10][11] Although our study supports a role of Strap in mitochondrial-dependent apoptosis, we cannot rule out the possibility that Strap, as a general stress-responsive p53 co-factor, may have a role in other p53 functions, such as p53-dependent necrosis. 36 It is also interesting to note that alterations in ATP levels would likely influence AMPK (AMP-activated protein kinase), which monitors cellular energy status.…”

“…L-Strap was prepared by fusing the Bcl2 mitochondrial targeting signal (DFSWLSLKTLLSLALV-GACITLGAYGHK) onto the C-terminal region of Strap in HA-WT Strap. 9,10 Antibodies. The following antibodies were used: Flag peptide M2 (Sigma), HA11 (Covance, Cambridge, UK), calnexin (Millipore, Nottingham, UK), cleaved PARP and cytochrome oxidase IV (Cell Signaling Technology, Leiden, The Netherlands), b-actin (Sigma), ATP synthase b-subunit (BD Pharmingen, Oxford, UK), PCNA, p53 and cytochrome c (Santa Cruz, Heidelberg, Germany) and Strap.…”

“…6,8 Strap is one such cofactor that regulates p53 transcriptional activity under a variety of cellular conditions. 9 Upon DNA damage, for example, it is phosphorylated by the DNA damage signalling ATM and Chk2 kinases, resulting in Strap stabilisation, altered cellular location and enhanced p53 activity. 10,11 An analysis of the three-dimensional structure of Strap highlighted its unusual domain organisation, being composed of tandem TPR motifs together with an OB-fold, with both domains required for it to function in the p53 response.…”