p53 isoforms have a high aggregation propensity, interact with chaperones and lack binding to p53 interaction partners

Brdar, A.; Osterburg, C.; Münick, P.; Machel, A. C.; Rathore, R.; Osterburg, S.; Yüksel, B.; Schäfer, B.; Desch, K.; Langer, J. D.; Dikic, I.; Dötsch, V.

doi:10.1101/2024.10.02.616239

bioRxiv · 10.1101/2024.10.02.616239

p53 isoforms have a high aggregation propensity, interact with chaperones and lack binding to p53 interaction partners

Brdar, A.·Osterburg, C.·Münick, P.·Machel, A. C.·Rathore, R.·Osterburg, S.·Yüksel, B.·Schäfer, B.·Desch, K.·Langer, J. D.·Dikic, I.·Dötsch, V.

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Abstract

The p53 transcription factor family consists of the three members p53, p63 and p73. Both p63 and p73 exist in different isoforms that are well characterized. Isoforms have also been identified for p53 and it has been proposed that they are responsible for increased cancer metastasis. In contrast to the p63 and p73 isoforms, which do not contain truncations in folded domains, most of the p53 isoforms contain only parts of either the DNA binding domain or the oligomerization domain. To better understand the effect of p53 isoforms in cancer we provide here a comprehensive biochemical characterization. With the exception of the {Delta}40p53 isoform none of the other variants can bind to DNA with high affinity and none can upregulate transcription. Probing with antibodies, DARPins and other interaction partners confirmed that isoforms harboring deletions in the DNA binding domain cannot interact specifically with them, but instead are bound to chaperones and other factors known to interact with misfolded proteins. Expression of isoforms with deletions in the DNA binding domain results in upregulation of cellular chaperones. If the expression level surpasses a threshold, the chaperone system can no longer keep these isoforms soluble resulting in aggregation and co-aggregation with other factors.

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Brdar, A., Osterburg, C., Münick, P., Machel, A. C., Rathore, R., Osterburg, S., Yüksel, B., Schäfer, B., Desch, K., Langer, J. D., Dikic, I., Dötsch, V.. 2024-10-06. p53 isoforms have a high aggregation propensity, interact with chaperones and lack binding to p53 interaction partners. https://doi.org/10.1101/2024.10.02.616239

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