Abstract

Bacterial signaling cascades have recently become of great relevance in the context of bacterial antibiotics resistance. Cyclic diadenylate monophosphate (c-di-AMP) is a key bacterial secondary messenger involved in growth, biofilm formation, virulence gene expression and others. The activation mechanisms of c-di-AMP receptors like the trimeric P II-like proteins upon messenger binding have, however, remained elusive due the pivotal role of highly flexible protein regions. Here, using solution NMR spectroscopy to elucidate the interplay between the ordered and disordered structural elements of the apo and messenger-bound forms of the 44 kDa homotrimeric P II-like signal transduction protein A (PstA), we reveal a sensitive modulation of the conformational ensemble of those extended loops thought to bind the downstream interaction partners by messenger association at the receptor core. The orchestration of the spatial properties of the loops, despite their retained internal dynamics, reveals the importance of allosteric effects even for disordered structural elements, whose steerable ensemble properties have long escaped the classical structural-biology understanding.