BBB Seminar: Øyvind Halskau
Interplay of non-native, dynamic and flexible protein states in protein-protein and protein-membrane interactions
Department of Biomedicine, University of Bergen
Protein structure-function relationships usually implicitly assume that function is derived from an ordered crystal-like state. While this is undoubtedly an assumption that holds for the majority of known cases, function – or dysfunction – may also stem from non-ordered states. According to a theoretical concept sometimes referred to as the Protein Trinity, function can arise from a disordered non-condensed state, a disordered condensed state, as well as the familiar ordered condensed state that we know from text-book structural biology. Transitions between these states are particularly important for reversible protein-membrane interactions and many-to-one interactions. Examining the HAMLET/α-Lactalbumin system in terms of low energetic folding barriers, membrane affinity and intermediately folded states have proven very fruitful for understanding the basis for the pharmacological action of HAMLET. We have shown that α-Lactalbumin has a surprisingly low folding barrier, a characteristic that made it possible to prepare the intermediately folded HAMLET conformation (Halskau et al., Proc Natl Acad Sci U S A. 2008, 105:8625). The results also shed light on why mutants generated to mimic the HAMLET conformation failed. Moreover, we have shown that an essential quality of HAMLET is its ability to bind to and disrupt membranes under physiological conditions (Mossberg et al., PLoS One. 2010, 5:e9384). Lastly, a hypothesis where the characteristics of HAMLET are explained in terms of a modulation of a propensity already found in native α-Lactalbumin is proposed.
Chair: Aurora Martinez, Department of Biomedicine