Lotz Rebecca, Osterburg Christian, Schäfer Birgit, Lu Xin, Dötsch Volker
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
Cell Death Discov. 2024 Dec 18;10(1):497. doi: 10.1038/s41420-024-02265-z.
The ASPP (apoptosis-stimulating protein of p53) family of proteins is involved in many cellular interactions and is starting to emerge as a major scaffolding hub for numerous proteins involved in cancer biology, inflammation and cellular integrity. It consists of the three members ASPP1, ASPP2 and iASPP which are best known for modulating the apoptotic function of p53, thereby directing cell fate decision. Germline mutations in iASPP have been shown to cause cardiocutaneous syndromes, a combination of heart and skin defects usually leading to death before the age of five. Mutations in iASPP causing these syndromes do not cluster in hot spots but are distributed throughout the protein. To understand the molecular mechanism(s) of how mutations in iASPP cause the development of cardiocutaneous syndromes we analysed the stability and solubility of iASPP mutants, characterized their interaction with chaperones and investigated their influence on NF-ĸB activity. Here we show that three different mechanisms are responsible for loss of function of iASPP: loss of the complete C-terminal domain, mutations resulting in increased auto-inhibition and aggregation due to destabilization of the C-terminal domain. In contrast to these germline mutations causing cardiocutaneous syndromes, missense mutations found in cancer do not result in aggregation.
ASPP（p53凋亡刺激蛋白）家族蛋白参与多种细胞相互作用，并开始成为癌症生物学、炎症和细胞完整性相关众多蛋白的主要支架中心。它由ASPP1、ASPP2和iASPP三个成员组成，它们最出名的是调节p53的凋亡功能，从而指导细胞命运决定。已表明iASPP中的种系突变会导致心脏皮肤综合征，这是一种心脏和皮肤缺陷的组合，通常导致五岁前死亡。导致这些综合征的iASPP突变并不集中在热点区域，而是分布在整个蛋白质中。为了了解iASPP突变导致心脏皮肤综合征发展的分子机制，我们分析了iASPP突变体的稳定性和溶解性，表征了它们与伴侣蛋白的相互作用，并研究了它们对NF-κB活性的影响。在这里，我们表明三种不同机制导致了iASPP功能丧失：完整C末端结构域的缺失、导致自抑制增加的突变以及由于C末端结构域不稳定而导致的聚集。与这些导致心脏皮肤综合征的种系突变不同，在癌症中发现的错义突变不会导致聚集。
