Structural insights into the high-efficiency catalytic mechanism of the sterileα-motif/histidine-aspartate domain-containing protein

Sterileα-motif/histidine-aspartate domain-containing protein (SAMHD1), a homo-tetrameric GTP/dGTP-dependent dNTP triphosphohydrolase, catalyzes the conversion of dNTP into deoxynucleoside and triphosphate. As the only characterized dNTP triphosphohydrolase in human cells, SAMHD1 plays an important role in human innate immunity, autoimmunity, and cell cycle control. Previous biochemical studies and crystal structures have revealed that SAMHD1 interconverts between an inactive monomeric or dimeric form and a dGTP/GTP-induced active tetrameric form. Here, we describe a novel state of SAMHD1(109-626 amino acids, SAMHD1C) that is characterized by a rapid initial hydrolysis rate. Interestingly, the crystal structure showed that this novel SAMHD1 tetramer contains only GTP and has structural features distinct from the GTP/dNTP-bound SAMHD1 tetramer. Our work thus reveals structural features of SAMHD1 that may represent one of its biological assembly states in cells.