In the field of biochemistry, PDK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, which is an enzyme encoded by the PDK1 gene in humans. It is related to the occurrence and development of melanoma. PDK1 stands for 3-phosphoinositide-dependent protein kinase 1. PDPK1 functions downstream of PI3K through the interaction of PDK1 with membrane phospholipids, including phosphatidylinositol (3,4) -bisphosphate and phosphatidylinositol(3,4,5)-triphosphate. PI3K indirectly regulates PDPK1 through phosphorylation of phosphatidylinositol, which in turn produces phosphatidylinositol (3,4) -bisphosphate and phosphatidylinositol (3,4,5) -triphosphate. However, PDPK1 is considered to have constitutive activity and does not always require phosphatidylinositol to exert its activity. Phosphatidylinositol only needs to be activated on the membranes of certain substrates, including AKT. However, PDK1 does not require membrane lipid binding to efficiently phosphorylate most of its substrate in the cytosol (rather than at the cell membrane).
Structure
The structure of PDK1 can be divided into two domains; a kinase or catalytic domain and a PH domain. The PH domain mainly plays a role in the interaction of PDK1 with phosphatidylinositol (3,4) -bisphosphate and phosphatidylinositol (3,4,5) -triphosphate, which is related to some membranes. The localization and activation of PDK1 substrates (including AKT) is important. The kinase domain has three ligand binding sites; a substrate binding site, an ATP binding site, and a docking site (also known as a PIF pocket). Several PDK1 substrates, including S6K and protein kinase C, need to bind at this docking site. It has been shown that small molecule allosteric activators of PDK1 selectively inhibit the activation of substrates that require docking site interactions. These compounds do not bind to the active site and allow PDK1 to activate other substrates that do not require docking site interaction. PDP1 has constitutive activity, and there is no known PDK1 inhibitor protein. It is believed that the activation of PDP1's main effector, AKT, requires the correct localization of the kinase and PH domains of PDP1 and AKT on the membrane.
Functions
PDK1 is a major kinase that is essential for activating AKT/PKB and many other AGC kinases (including PKC, S6K, SGK). The important role of PDK1 is through a variety of growth factors and hormones (including insulin signaling) activated signaling pathways. The death of mice lacking PDPK1 during early embryonic development suggests that the enzyme is essential for transmitting the growth-promoting signals necessary for normal mammalian development. Mice lacking PDK1 lost approximately 40% of their body weight, were less tolerant to glucose, and were resistant to cancer caused by PI3K pathway overactivation (PTEN+/-).
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