Holding hands to help cells share information and make decisions.

What is it about?

An important part of biology is the coordinated decisions cells make to change their structures and activities. To make these decisions, cells pass messages through each other through signaling pathways. These messages are transmitted and interpreted by assembling and disassembling protein complexes. One such complex is the "Notch" transcription complex, which turns on genes in cells when told to do so by their neighboring cells. The Notch transcription complex is built from three proteins that grasp each other at multiple sites, like a two people holding each other with both hands, and a third grabbing one of those handshakes to keep it fast. Here we developed new methods and models to learn how this unique "bivalent" grasp helps form the complex.

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Why is it important?

In addition to providing important insights into this bivalent complex, our work lays out a new approach to measuring these interactions, including ways to measure the strength of interaction of three proteins at once by measuring their heats of interaction, and a way to determine how grasping with two hands is more stable than with just one. Interestingly, the connection between the two "hands" in one of the proteins is not a structured connection, but is made of a disordered protein chain. Our work helps show how a disordered chain can lead to strong interactions at distant sites. The framework we develop should be useful for studying other multi-protein complexes.

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