Research Highlights

Valerie Khayyo

 

Lipins complete the second to last step of triglyceride production, which is the main source of energy storage in cells. Mutations exist that interrupt lipin function, where the body loses its ability to store fat properly, thus triggering a wide variety of metabolic-related conditions including fatty liver dystrophy, insulin resistance, and improper fat storage. Since the discovery of lipins in 2001, research has been done to understand their importance functionally. However, structural information was lacking due to biochemical challenges with the enzyme stability. In this paper we successfully solve the first crystal structure of an enzyme from the lipin/PAP family. Tt Pah2 provides a catalytic model to visualize the functional core of the more complex mammalian lipins. We used  X-ray crystallography, mass spectrometry and biochemical assays to visualize the structure, characterize how lipins bind to membranes, and structurally map key mutations involved in lipin dysfunction that results in diseases.

 

Forrest Bowling

 

 

Andreyah Pope 

Retinal orientation and interactions in rhodopsin reveal a two stage trigger mechanism for activation. Nature Communications 7, 12683

 The 11-cis retinal chromophore of the visual receptor rhodopsin is tightly packed within the protein’s interior. Solid-state NMR spectroscopy is used to define the orientation and interactions of the retinal chromophore in the active Metarhodopsin II intermediate trapped along its photoreaction pathway. The orientation of the retinal differs from that in recent active-state rhodopsin crystal structures. We show that retinal isomerization generates strong steric interactions with transmembrane helices H5 and H6 via contacts with the ionone portion of the retinal, while deprotonation of the retinal Schiff base triggers the rearrangement of hydrogen-bonding interactions involving residues on helix H6 and within the second extracellular loop. We integrate these observations with previous structural and functional studies to propose a two-stage mechanism for rhodopsin activation to describe how absorbed light energy is channeled into the protein to direct the known outward rotation of transmembrane helix H6, a hallmark of active G protein-coupled receptors.