具有种系PTEN肿瘤抑制变异体的个体具有PTEN错构瘤肿瘤综合征(PHTS)。临床上,PHTS有不同的表现;有不同的受PHTS影响的个体的子集,例如那些被诊断患有自闭症谱系障碍(ASD)或癌症的人。目前尚不清楚为什么一个基因的突变会导致这种看似不同的表型。因此,我们试图确定是否有可能预测给定的受PHTS影响的个体的ASD先验风险,癌症,或者两种表型的共同出现。通过整合对人类相互作用组进行的网络邻近分析,分子模拟,和残余相互作用网络,我们证明了构象动力学在与ASD或癌症相关的种系PTEN变异体的结构通讯和长程变构调节中的作用.我们表明,PTEN相互作用组与ASD和癌症相互作用组共享显著重叠,提供基于网络的证据,证明PTEN在这两种疾病的生物学中起着至关重要的作用。重要的是,这一发现表明,种系PTEN变异可能会以不同方式扰乱ASD或癌症网络,因此在任何时候都有利于一种疾病的结果。此外,蛋白质动态结构网络分析揭示了由高度保守的功能残基介导的小世界结构通讯和PTEN的潜在变构调节。我们确定了一个显著的结构通讯途径,该途径延伸到仅癌症突变的结构域间接口。相比之下,对于仅ASD突变,结构通讯途径主要局限于磷酸酶结构域.我们的综合方法支持相关构象状态的预测和潜在调节,这些构象状态会影响与导致PTEN-ASD或PTEN癌症表型的突变效应相关的结构交流和远程扰动。
Individuals with germline PTEN tumor-suppressor variants have PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has variable presentations; there are distinct subsets of PHTS-affected individuals, such as those diagnosed with autism spectrum disorder (ASD) or cancer. It remains unclear why mutations in one gene can lead to such seemingly disparate phenotypes. Therefore, we sought to determine whether it is possible to predict a given PHTS-affected individual\'s a priori risk of ASD, cancer, or the co-occurrence of both phenotypes. By integrating network proximity analysis performed on the human interactome, molecular simulations, and residue-interaction networks, we demonstrate the role of conformational dynamics in the structural communication and long-range allosteric regulation of germline PTEN variants associated with ASD or cancer. We show that the PTEN interactome shares significant overlap with the ASD and cancer interactomes, providing network-based evidence that PTEN is a crucial player in the biology of both disorders. Importantly, this finding suggests that a germline PTEN variant might perturb the ASD or cancer networks differently, thus favoring one disease outcome at any one time. Furthermore, protein-dynamic structural-network analysis reveals small-world structural communication mediated by highly conserved functional residues and potential allosteric regulation of PTEN. We identified a salient structural-communication pathway that extends across the inter-domain interface for cancer-only mutations. In contrast, the structural-communication pathway is predominantly restricted to the phosphatase domain for ASD-only mutations. Our integrative approach supports the prediction and potential modulation of the relevant conformational states that influence structural communication and long-range perturbations associated with mutational effects that lead to PTEN-ASD or PTEN-cancer phenotypes.