In contrast, IP 3 diffuses throughout the cytosol where it binds to IP 3 receptors embedded in endoplasmic reticulum leading to mobilization of sequestered calcium. Diacylglycerol is retained within membranes where it recruits and activates numerous proteins including conventional isoforms of protein kinase C. The 13 phospholipase C (PLC) isozymes expressed in humans preferentially hydrolyze the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP 2) to generate the second messengers diacylglycerol and inositol 1,4,5-trisphosphate (IP 3) ( Harden and Sondek, 2006 Kadamur and Ross, 2013). It is a first step toward designing new drugs that alter the activity of this enzyme, which may ultimately be useful to treat cancer and other diseases. provides a framework to understand how cells control PLC-γ1. In particular, these mutations disrupt the interactions between elements that usually hold the two lobes together, causing the enzyme to activate more easily. The three-dimensional structure also helps to understand how mutations identified in certain cancers may activate PLC-γ1. The findings suggest that when the phosphate group attaches to PLC-γ1, it triggers a large shape change that shifts the second lobe away from the active site to allow lipids to bind. This reveals that PLC-γ1 has two major lobes: one contains the active site that modifies lipids, and the other sits on top of the active site to prevent lipids from reaching it. determine in great detail the three-dimensional structure of the autoinhibited form of the enzyme using a method known as X-ray crystallography. However, it remains unclear how autoinhibition suppresses the activity of the enzyme, and how it is stopped by the addition of the phosphate group. When activating signals are present, a phosphate group serves as a ‘chemical tag’ and is added onto PLC-γ1, allowing the enzyme to bind to lipids.įailure in the regulation of PLC-γ1 or other closely related enzymes may lead to conditions such as cancer, arthritis and Alzheimer’s disease. This prevents the enzyme from binding to its targets, which are fat molecules known as lipids. When activating signals are absent, PLC-γ1 usually inhibits its own activity, a mechanism called autoinhibition. One such enzyme is phospholipase C-γ1 (PLC-γ1), which controls how cells grow, divide and migrate. Many enzymes are poised to receive signals from the surrounding environment and translate them into responses inside the cell. The model also explains why mutant forms of the PLC-γ isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease. Notably, an interlinked set of regulatory domains integrates basal autoinhibition, tyrosine kinase engagement, and additional scaffolding functions with the phosphorylation-dependent, allosteric control of phospholipase activation. Here, we describe the first high-resolution structure of a full-length PLC-γ isozyme and use it to underpin a detailed model of their membrane-dependent regulation. Although structures of isolated domains from PLC-γ isozymes are available, these structures are insufficient to define how release of basal autoinhibition is coupled to phosphorylation-dependent enzyme activation. In turn, aberrant activation of PLC-γ1 and PLC-γ2 is implicated in inflammation, autoimmunity, and cancer. Direct activation of the human phospholipase C-γ isozymes (PLC-γ1, -γ2) by tyrosine phosphorylation is fundamental to the control of diverse biological processes, including chemotaxis, platelet aggregation, and adaptive immunity.
0 Comments
Leave a Reply. |