KRS Research Program

KRS and the Multisynthetase Complex (MSC)

As a member of the eukaryotic ARS family lysylRS (KRS) contains a catalytic domain responsible for amino acid acylation and it also has an N-terminal extension and an anticodon binding domain.  Under certain conditions, both of these non-catalytic domains can become exposed on the cell surface.

  • KRS charges lysyl-tRNA with lysine for translation and is a subunit of the MSC.
  • Upon laminin stimulation in response to injury, p38MAPK phosphorylates at T52 of KRS casuing dissociation from the MSC and mobilization to the cell surface.
  • The 67LR laminin receptor binds laminin and induces inappropriate cell migration with pathological implications.  KRS binds to 67LR, preventing Nedd4-mediated ubiquitination to 67LR to extend the membrane stability of 67LR.
  • The result of these processes is that KRS enhances laminin-induced cell migration via controlling 67LR stability.
  • Inhibition of the KRS cell surface functions inhibits cellular proliferation and macrophage migration. Excubio has developed a series of novel humanized antibody molecules that act on this pathway and serve to block the KRS/67LR interaction by binding to KRS localized on the cell surface. Our lead high affinity antibody is undergoing preclinical optimization and development with the potential to be a new approach to the treatment of fibrosis.
  • Current Excubio development efforts are focused on fibrosis in the areas of pulmonary artery hypertension, idiopathic pulmonary fibrosis and of other fibrotic diseases, including liver, kidney and Alport syndrome.
  • Development has been initiated with a focus on Pulmonary Arterial Hypertension (PAH). Our studies include assessing the effects of the antibody in both the MCT-induced PAH rat model and the Sugar hypoxia rat model. The antibody shows a significant improvement in various PAH measurements, e.g. right ventricular end-systolic pressure and cardiac output, compared to controls when administered in both preventative and treatment mode. Our data indicate that the antibody has an enhanced efficacy compared to sildenafil, a standard of care in PAH. Moreover, histopathological analysis indicates that the antibody can reverse the effects of fibrosis when administered in treatment mode. We also have additional data in a lung infiltration model and in a liver fibrosis model.

KRS Domains

KRS ABD (anticodon-binding domain) interacts with 37LRP (monomeric laminin receptor)

  • N-terminal extension (N-ext, 1–72)
  • Anticodon-bindingdomain (ABD, 73–209) 
  • Catalytic domain (CD,220-597)
  • T52: Point of cell stimulant mediate phosphorylation