Researchers at Stony Brook University are now able to answer many long-standing questions about the formation of triglyceride molecules since they were able to visualize the structure of the enzyme lipin, which performs a critical production step. The results of this new study â published recently in Nature Communication through an article entitled “Crystal structure of a lipin / Pah acid phosphatidic phosphataseââHelp scientists better understand how lipins regulate triglyceride production. In addition, the structure also provides scientists with information on why mutations in the enzyme cause loss of activity that leads to abnormal production of triglycerides involved in heart disease, obesity, and diabetes.
“This structure answers a long-standing question about how two essential regions, N-lip and C-lip, which are located at opposite ends of this protein in humans, come together to form a functional enzyme to help making triglycerides, âexplained Mike Airola, PhD, assistant professor in the department of biochemistry and cell biology at Stony Brook University. “Using this structure also helps us understand how the protein interacts with membranes, which is essential for regulating its activity and the production of triglycerides.”
Lipins complete the penultimate step in the production of triglycerides. But when mutations disrupt lipid functions, the body loses its ability to properly store fat, potentially triggering a wide variety of metabolic conditions. Scientists have unsuccessfully attempted to create the first visual structure, a lipin enzyme since these enzymes were identified in 2001. The present study successfully describes the first crystal structure of a specific enzyme called lipin PAP.
âTo understand how N-Lip and C-Lip combine for PAP function, we determined the crystal structures of Tetrahymena thermophila Pah2 (tt Pah2) which directly merges N-Lip and C-Lip, âthe authors wrote. “tt Pah2 adopts a two-domain architecture where N-Lip combines with part of C-Lip to form an immunoglobulin-like domain, and the remaining C-Lip forms a HAD-like catalytic domain. An N-Lip C-Lip fusion of mouse lipin-2 is catalytically active, suggesting that mammalian lipins function with the same domain architecture as tt Pah2. “
The team used X-ray crystallography, mass spectrometry and biochemistry to visualize the structure, which represents the active state of a lipin enzyme during the production of triglycerides, as well as its other functions, namely l assembly of lipoproteins and cell signaling.
Study principal investigator Valerie Khayyo, a Stony Brook graduate student in the Biochemistry and Structural Biology program, added that the structure allows researchers to understand and see specific mutational changes in the building blocks of acids. amino lipids that cause disease.
Khayyo noted that mutations in lipins are also increasingly identified in patients with muscle disorders, such as statin-induced myopathy and extreme cases of infantile rhabdomyolysis.
Overall, Airola says the structure and study consolidates many previous observations into a unifying framework and sets the stage for scientists to resolve several important remaining questions regarding lipid regulation.
“This [data] illustrates the mechanisms of lipin / Pah PAP function, membrane association and lipid-related pathologies â, the authors concluded.