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Structural Insights into the High-efficiency Catalytic Mechanism of the Sterile ?-Motif/Histidine-Aspartate Domain-containing Protein.


ABSTRACT: Sterile ?-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. The biochemical and structural information generated by the present study not only provides an ordered pathway for the assembly and activation of SAMHD1 but also provides insights into the potential mechanisms of the high-efficiency catalytic activity of this enzyme family in vivo.

SUBMITTER: Li Y 

PROVIDER: S-EPMC4705945 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Structural Insights into the High-efficiency Catalytic Mechanism of the Sterile α-Motif/Histidine-Aspartate Domain-containing Protein.

Li Yanhong Y   Kong Jia J   Peng Xin X   Hou Wen W   Qin Xiaohong X   Yu Xiao-Fang XF  

The Journal of biological chemistry 20151005 49


Sterile α-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 dimeri  ...[more]

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