Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
Department of Biochemistry and Biotechnology, University of Gujrat, Hafiz Hayat Campus, Gujrat, Punjab 50700, Pakistan.
Hum Mol Genet. 2022 Jul 7;31(13):2236-2261. doi: 10.1093/hmg/ddac029.
Novel protein kinase C (nPKC) family member, protein kinase C epsilon (PKCε) is an AGC kinase superfamily member. It is associated with neurological and metabolic diseases as well as human cancers. No study so far has been conducted to identify genetic variations and their effect on PKCε folding and functioning. The present study aimed to identify mutational hotspots in PKCε and disease-causing non-synonymous variants (nsSNPs) along with the investigation of nsSNP impact on protein dynamics. Twenty-nine in silico tools were applied to determine nsSNP deleteriousness, their impact on protein dynamics and disease association, along with the prediction of PKCε post-translational modification (PTM) sites. The present study's outcomes indicated that most nsSNPs were concentrated in the PKCε hinge region and C-terminal tail. Most pathogenic variants mapped to the kinase domain. Regulatory domain variants influenced PKCε interaction with molecular players whereas kinase domain variants were predicted to impact its phosphorylation pattern and protein-protein interactions. Most PTM sites were mapped to the hinge region. PKCε nsSNPs have an association with oncogenicity and its expression dysregulation is responsible for poor overall survival. Understanding nsSNP structural impact is a primary step necessary for delineating the relationship of genetic level differences with protein phenotype. The obtained knowledge can eventually help in disease diagnosis and therapy design.
新型蛋白激酶 C（nPKC）家族成员，蛋白激酶 C ɛ（PKCε）是 AGC 激酶超家族成员。它与神经和代谢疾病以及人类癌症有关。迄今为止，尚无研究旨在鉴定 PKCε 折叠和功能的遗传变异及其影响。本研究旨在鉴定 PKCε 中的突变热点和致病非同义变异（nsSNP），并研究 nsSNP 对蛋白质动力学的影响。应用 29 种计算工具来确定 nsSNP 的有害性、它们对蛋白质动力学和疾病的影响，以及 PKCε 翻译后修饰（PTM）位点的预测。本研究的结果表明，大多数 nsSNP 集中在 PKCε 的铰链区和 C 末端尾部。大多数致病性变异位于激酶结构域。调节结构域的变异影响 PKCε 与分子伴侣的相互作用，而激酶结构域的变异被预测会影响其磷酸化模式和蛋白质-蛋白质相互作用。大多数 PTM 位点映射到铰链区。PKCε 的 nsSNP 与致癌性有关，其表达失调导致整体生存率降低。了解 nsSNP 的结构影响是阐明遗传水平差异与蛋白质表型关系的必要步骤。获得的知识最终有助于疾病诊断和治疗设计。
