Author response: Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1
Year: 2013
Type: peer-review
Abstract: Individual cells within the human body must grow, divide or specialize to perform the tasks required of them. The fates of these cells are often directed by proteins in the Ras family, which detect signals from elsewhere in the body and orchestrate responses within each cell. The activities of these proteins must be tightly controlled, because cancers and developmental diseases can result if Ras proteins are not properly regulated. Binding to the small molecule GTP activates Ras and causes conformational changes that allow it to interact with other proteins in various signaling pathways in the cell. GTP is loaded into Ras by proteins called nucleotide exchange factors, which can replace ‘used’ nucleotides with ‘fresh’ ones to activate Ras. These nucleotide exchange factors are also tightly regulated. For example, the genes for many exchange factors are only switched on after particular signals are received, which can restrict their presence to defined times and locations (e.g., cells or tissues). Also, when activating signals are absent, nucleotide exchange factors commonly reside in the cytoplasm, whereas the Ras proteins remain bound to lipid membranes inside the cell. RasGRP1 is a nucleotide exchange factor that controls the development of immune cells, and leukemia and lupus can result if it is not regulated correctly. However, many questions about RasGRP1 remain unanswered, including how it is able to remain inactive, and how it is activated by various different signals. Iwig et al. have now revealed the mechanisms through which RasGRP1 suppresses Ras signaling in immune cells by solving the structures of two fragments of RasGRP1 and then using a combination of structural, biochemical and cell-based methods to explore how it is activated. These analyses revealed that inactive RasGRP1 adopts a conformation in which one of its regulatory elements blocks access to the Ras binding site. Surprisingly, RasGRP1 can form dimers; this hides the portions of the protein that associate with the membrane and thereby keeps RasGRP1 away from Ras. Iwig et al. also found that two signals, calcium ions and a lipid called diacylglycerol, overcome these inhibitory mechanisms by changing the conformation of RasGRP1 and recruiting it to the membrane. These studies provide a framework for understanding how disease-associated mutations in RasGRP1 bypass the regulatory mechanisms that insure proper immune cell development, and will be critical for developing therapeutic agents that inhibit RasGRP1 activity.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W2988824082