Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding and Binding Mechanism •Tollip TBD is a disordered domain that partially folds when bound to Tom1 GAT •Tom1 GAT also directly binds to the Tollip C2 domain •Binding of Tom1 to Tollip inhibits binding of Tollip to PtdIns(3)P •Tollip TBD plays a major role in Tom1’s inhibitory function
It has important implications for Rx of allergies, heart disease, cancer types. The discovery explains how 2 particular proteins, Tollip and Tom1, work together to contribute to the turnover of cell-surface receptor proteins that trigger inflammation. “At appropriate levels, the inflammatory response protects your body from foreign materials, but if it is not properly regulated it can lead to severe, chronic conditions.” said A/Prof Daniel Capelluto.
Inflammation plays a role in major health problems such as heart disease, diabetes, Alzheimer’s disease, and cancer, as well as psychiatric diseases such as depression and autism spectrum disorder, according NIH. The discovery by Virginia Bioinformatics Institute researchers reveals protein structural changes within cells that could help inform treatments.
When the body is attacked by microbes, specialized cells secrete pro-inflammatory signals recognized by interleukin-1 receptors on the surface of specialized cells, triggering release of additional pro-inflammatory molecules which amplify the response against pathogens. These receptors continue to promote inflammation as long as they detect that initial “alert” signal. When a healthy level of inflammation is reached, the receptor proteins need to be removed and delivered to endosomes for containment and further clearance.
Using a combination of techniques, eg 2D and 3D NMR spectroscopy, surface plasmon resonance, and fluorescence cell microscopy, they determined Tollip’s association with Tom1 drastically changes Tollip’s structure, forming a unit that can potentially transport cargo much more efficiently than either protein on its own. Tollip contains a functional module C2, which anchors the protein to the surface of the endosomal membrane to pick up cargo. However, with C2 engaged in holding Tollip’s position, the protein’s load-bearing capacity is limited.
But when Tom1 binds to Tollip, Tollip’s C2 domain is no longer directly associated with the endosomal membrane, shifting its function from “landing gear” to “cargo bay.” The resulting unit can carry larger loads and assist in the clearance of unneeded receptor proteins efficiently.
The discovery expands understanding of how the body regulates its inflammatory response and may inform efforts to treat diseases associated with chronic inflammation eg heart disease, stroke, and colon cancer  http://www.eurekalert.org/pub_releases/2015-08/vt-src082115.php
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