Molecular Details of the Mechanism of PS Recognition by TIM Proteins

Abstract

Accumulating evidence suggests that an immune response can be triggered by the presence of abnormal lipid components, such as phosphatidylserine (PS), in the outer leaflet of the cellular membrane. The T-cell immunoglobulin and mucin domain (TIM) family of proteins recognize PS exposed on the surface of the membrane. TIM proteins are expressed by numerous cell types, and despite their close structural similarity, they are involved in triggering different immune responses. These specific roles have been attributed to different factors, including differential binding modes of TIM proteins to anionic membranes and their variable sensitivity to lipid composition of the membrane.In order to study the mechanism of membrane binding by TIM proteins, we have performed MD simulations of TIM1 and TIM3 employing our enhanced-dynamics HMMM membrane model. For each protein, we have performed a total of 30 independent simulations with different lipid compositions (1:1 PC:PS and 7:3 PC:PS), providing robust statistics to characterize the membrane-bound form of these proteins. The results suggest that, despite the overall structural similarity, TIM1 and TIM3 establish different interactions with the membrane upon binding. Moreover, simulations show that in addition to the PS-binding pocket found in TIM proteins, other specific protein-membrane ionic interactions can be formed in each case, suggesting a molecular basis for their different biological roles.In addition to MD simulations, the orientation of TIM1 and TIM3 in model PS-containing membranes has been characterized using X-ray scattering. The agreement between the X-ray experiments and the MD simulations provide a detailed description of the membrane-binding mechanism of TIM proteins.