The HAMP signal-conversion domain: static two-state or dynamic three-state?

The 50-residue HAMP domain converts input signal into output response in a variety of transmembrane signal transduction proteins, including methyl-accepting chemotaxis proteins and histidine kinases. HAMP domains are present in many other contexts as well. Despite focused study over the past decade, the question remains: How does this small domain play such a large role for so many different proteins? Analysis of structural models for the Afl1503 and Aer2 HAMP domains has generated hypotheses in which the HAMP domain assumes either of two discrete forms that generate opposing signal output. In contrast, genetic analysis of the HAMP domain from the Tsr methyl-accepting chemotaxis protein resulted in a distinct hypothesis, the biphasic dynamic bundle. In this hypothesis, signalling involves differential packing stabilities of the HAMP domain four-helix bundle, marked by at least three distinct states. Here I summarize and compare these hypotheses in the context of a deletion analysis that further explores the biphasic dynamic bundle hypothesis.