Foldable Detergents for Membrane Protein Study: Importance of Detergent Core Flexibility in Protein Stabilization. Issue 21 (15th March 2022) - Ghani, Lubna
Abstract: Membrane proteins are of biological and pharmaceutical significance. However, their structural study is extremely challenging mainly due to the fact that only a small number of chemical tools are suitable for stabilizing membrane proteins in solution. Detergents are widely used in membrane protein study, but conventional detergents are generally poor at stabilizing challenging membrane proteins such as G protein‐coupled receptors and protein complexes. In the current study, we prepared tandem triazine‐based maltosides (TZMs) with two amphiphilic triazine units connected by different diamine linkers, hydrazine (TZM−Hs) and 1, 2‐ethylenediamine (TZM−Es). These TZMs were consistently superior to a gold standard detergent (DDM) in terms of stabilizing a few membrane proteins. In addition, the TZM−Es containing a long linker showed more general protein stabilization efficacy with multiple membrane proteins than the TZM−Hs containing a short linker. This result indicates that introduction of the flexible1, 2‐ethylenediamine linker between two rigid triazine rings enables the TZM−Es to fold into favourable conformations in order to promote membrane protein stability. The novel concept of detergent foldability introduced in the current study has potential in rational detergent design and membrane protein applications. Abstract : The tandem triazine‐based maltoside with the ethylene diamine linker (i. e., TZM−E9) conferred markedly enhanced stability to the tested membrane proteins compared to the hydrazine linker analog and the conventional dodecyl maltoside (DDM): prokaryotic leucine transporter (LeuT), human β2 adrenergic receptor (β2 AR), and mouse μ‐opioid receptor (MOR). The favorable behaviors of this detergent for membrane protein stability are mainly due to its foldable nature, originating from the flexible ethylene diamine linker present between the two triazine units.