Translocation of PKC theta to plasma membrane

DAG along with intracellular calcium signals cooperatively to activate PKCs, which then trigger other pathways such as the NF-kB pathway, ultimately leading to mast cell (MC) degranulation and cytokine production (Wu 2011). PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates.<br>MCs express several Protein kinase C (PKC) isozymes and these kinases are involved in both the activation and termination of the degranulation process. PKC-delta is a negative regulator of FCERI mediated mast cell degranulation, whereas PKC-theta facilitates in degranulation (Leitges et al. 2002, Liu et al. 2001). In response to FCERI activation PKC-theta translocates to membrane by binding to DAG with its C1 domain. PKC-theta exists in two conformations closed/inactive and open/active state. In resting state, PKC-theta is autoinhibited where the pseudosubstrate sequence in the N-terminal regulatory region of PKC-theta forms intramolecular interaction with the substrate-binding region in the catalytic domain. This prevents the catalytic domain gaining access to substrates. The allosteric change of PKC-theta from closed to open state involves two important mechanisms: DAG binding to the C1 domains and autophosphorylation of T538 on the activation loop. Interaction with DAG induces conformational change resulting in the exposure of the activation loop of PKC-theta (Wang et al. 2012, Melowic et al. 2007).

细胞内钙信号与二酰基甘油（DAG）协同作用激活蛋白激酶C（PKC），进而触发如核因子-κB（NF-kB）途径等其他信号通路，最终导致肥大细胞（MC）脱颗粒和细胞因子产生（Wu 2011）。PKC theta 属于Ca2+非依赖性和DAG依赖性新型PKC亚家族成员，主要表达于T细胞中。它包含N端C2样结构域、伪底物（PS）、DAG结合（C1）结构域和C端激酶结构域。伪底物序列类似于理想底物，但其包含一个丙氨酸残基而非底物丝氨酸残基，在静息状态下与激酶结构域结合。因此，PKC theta 被维持在闭合的非活性状态，无法与细胞底物接触。<br>肥大细胞表达多种蛋白激酶C（PKC）同工酶，这些激酶参与脱颗粒过程的激活和终止。PKC-delta 是FCERI介导的肥大细胞脱颗粒的负调节因子，而PKC-theta 则促进脱颗粒（Leitges 等，2002；Liu 等，2001）。在FCERI激活的响应下，PKC-theta 通过其C1结构域与DAG结合，转位到膜上。PKC-theta 存在两种构象：闭合/非活性状态和开放/活性状态。在静息状态下，PKC-theta 自抑制，其中PKC-theta N端调节区域中的伪底物序列与催化域的底物结合区域形成分子内相互作用，从而阻止催化域接触底物。PKC-theta 从闭合到开放状态的别构变化涉及两种重要机制：DAG 结合到C1结构域和激活环上的T538自磷酸化（Wang 等，2012；Melowic 等，2007）。