A single twist in a protein loop—a rare chemical bond that forces a kink into a plant hormone receptor—determines whether the hormone auxin can switch genes on or off. This matters because auxin controls how plants grow, flower, and respond to stress. Synthetic auxin herbicides, worth nearly $4 billion a year globally, exploit this system to kill weeds. But some weeds have evolved resistance through mutations in the degron—the twisted loop region—threatening food production in several countries. Researchers do not yet understand how the twist forms, how the surrounding disordered protein region stabilises it, or how resistance mutations affect the plant’s survival when herbicides are not present. If successful, this project will reveal the molecular mechanics that made auxin signalling central to land plants’ evolutionary success. That knowledge could guide smarter herbicide stewardship—predicting which resistance mutations are likely to persist and how to rotate compounds to slow their spread. The work is fundamental science: it asks how a single chemical bond’s shape controls a signalling system that underpins global agriculture. Past discoveries about protein disorder and rare bond conformations have opened unexpected routes to drug design and synthetic biology; this project could do the same for crop protection.
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Auxin is central for the life of land plants. Moreover, herbicides based on auxin are fundamental for global food security. The auxin system consists of a complex of a receptor protein, the auxin molecule, and a co-receptor protein of the Aux/IAA family. In the available crystal structures of this complex, a region of the co-receptor known as the degron is found as a loop filling the binding pocket. The heart of the degron is a sequence (GWPPV) conserved across land plants, and the degron is locked in place by the W-P bond being in the cis conformation giving a twist to form this loop. In general, peptide bonds are almost always trans. Uniquely, our recent work showed that 50% of the unbound degron exists as the WcisP conformer. Our first hypothesis is that the flanking sequences of the degron contribute to the unusual stability of this WcisP bond, even though the sequence of amino acids around the degron region is predicted to be disordered. Intrinsically disordered regions (IDR) are common in proteins and despite their lack of formal structure IDRs are essential for function. Our recent work has shown that the IDR of Aux/IAA17 exists as an ensemble of dissimilar conformations, offering a series of different surfaces for protein-protein interactions. The auxin co-receptor complex is part of a ubiquitin E3 ligase enzyme and ubiquitylation efficacy of many E3 ligases is determined not only by target binding, but also by cis-acting regulatory interactions. Our second hypothesis is that there are unknown regulatory proteins which bind to and promote certain structural elements in the IDR of the Aux/IAAs and affect auxin sensitivity. Interestingly, the flanking sequences in the IDR around some auxin degrons have been associated with field resistance to auxin herbicides in several weeds, which is a serious threat to food sufficiency in some countries. Our third objective is to understand the molecular basis of these resistances and their durability outside selective pressure, so that we may promote the best compound stewardship practices. We will: Use molecular dynamics simulations and receptor-binding assays to examine promotion of the cis bond in the degron. We will also establish how structural plasticity is supported by flanking sequences. This will identify the key to the molecular basis of auxin signalling which contributed to the ascent of land plants. Use constructs of Aux/IAA IDRs fused with neonGreen fluorescent protein to identify interacting proteins using proteomics. This will discover cis-acting regulators of auxin-mediated signalling. Mutations in several auxin herbicide resistances map to the degron region of weed Aux/IAAs. We will measure how degron plasticity, signalling efficiency and cis regulation affect fecundity with and without selective pressure of auxin herbicides. This will determine the molecular drivers behind the emergence of resistance-conferring mutations. Combined, these WPs will give unprecedented insights into the biophysics, biochemistry and applied biology of the auxin degron and the role its IDR plays in auxin signalling. Moreover, this new understanding will provide a knowledge-rich rationale for future stewardship of synthetic auxins which currently have a global value as selective herbicides of close to $4 Bn a year.
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