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Abstract:
HAMP domains are small, dimeric, four-helical bundles found exclusively in a class of signalling proteins in prokaryotes, unicellular eukaryotes, fungi, and plants. For over a decade - and several Alpbach meetings - we have been pursuing a model of HAMP-mediated signal transduction via transitions in coiled-coil packing modes. But how would this project have played out in the alphaFold era? Do alphaFold models have the level of detail needed to resolve such mechanistic issues? Here I review the HAMP project under the alphaFold paradigm and in particular the case of polyHAMP arrays, tracts of up to 57 contiguous HAMP domains that occur in chemotaxis and histidine kinase signalling proteins. Experimental structures have characterised polyHAMP arrays as tightly organised, rod-shaped proteins with an alternating pattern of two distinct HAMP forms along the array. These forms are distinguished by coiled-coil packing modes, including variants of complementary x-da packing with opposite rotation states to those previously observed in canonical HAMPs. Modelling with AlphaFold2 suggests that this alternating
pattern is the hallmark of poly-HAMP arrays, supporting our model of signalling via axial
helix rotation.
