Structural And Functional Versatility of Interferon‐Inducible GTPases

Abstract

Listen

Translate article

GTP triphosphatases (GTPases) have been meticulously documented for their roles to regulate multiple cellular processes spanning from cell mobility, membrane fusion and fission, to cytokinesis and vesicle transport. Interferon (IFN)‐inducible GTPases, consisting of more than forty members in human and mice, are among the most highly expressed interferon stimulated genes (ISGs), sometimes accounting for twenty percent of all proteins induced by IFN‐γ. Recent genetic and cell studies start to reveal the important roles of IFN‐inducible GTPases in restriction and elimination of pathogens, yet the molecular mechanisms are largely unclear. Using a combination of biochemical, structural, biophysical, and computational tools, we are investigating the functional forms of two IFN‐inducible GTPases, GBP2 and IRGM, and the mechanisms governing their activation. We established the relationship between nucleotide binding and the oligomeric status of GBP2. A combination of X‐ray crystallography, electron microscopy, and molecular dynamics captured GBP2 conformational changes along the full trajectory of GTP binding and hydrolysis. Structure‐guided mutagenesis validated the roles of key residues in nucleotide binding pocket. In contrast to the dynamic nature of GBP2, IRGM assumed a highly stable oligomeric state that possessed intrinsic affinity towards lipids. In conclusion, GTP binding and hydrolysis regulate the oligomeric status of interferon‐inducible GTPases and subsequential effector molecule binding.Support or Funding InformationNIAID R00AI108793 “Dissecting inflammasome anatomy: mechanistic studies and potential intervention”; Florida State University startup fundsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.