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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]

PMID: 26438820

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Project description:Abstract Introduction: SAMD9 variants are associated with colon, breast and lung tumors. SAMD9 mutations result in adrenal hypoplasia, suggesting its importance in adrenal development. We investigated the contribution of abnormal expression of SAMD9 and its homologous, SAMD9L, to the pathogenesis of pediatric adrenocortical tumors (pACT) Objective: To evaluate the involvement of SAMD9 and SAMD9L in normal human adrenal cortex development and adrenocortical tumorigenesis, as well as to evaluate their association with tumor presentation and patient outcome. Methods: pACT samples (n= 72), normal pediatric adrenal cortices (n= 11), and normal fetal and post-natal adrenals (20 weeks of gestation to 10 years of age; n= 51) were enrolled. Protein expression of SAMD9 (immunohistochemistry) and SAMD9/SAMD9L mRNA levels were evaluated (qPCR). The associations between SAMD9/SAMD9L expression in pACT with tumor presentation (P53 p.R337H genotype and metastasis occurrence) and patient outcome (Overall (OS) and Disease-Free Survival) were analyzed. In silico, publicly available data from pediatric patients with ACT available in the Gene Expression Omnibus were used to evaluate the aforementioned associations with SAMD9 (GSE76021) and SAMD9L (GSE76019) mRNA levels. In vitro, SAMD9 subcellular localization pattern was investigated in the ACT cell line NCI-H295R (immunofluorescence). Results: Nuclear and cytoplasmic SAMD9 expression was observed throughout all different phases of adrenal development evaluated. However, in pACT samples, 26% presented nuclear and 86% cytoplasmic immunostaining. In line, NCI-H295R cells presented mostly cytoplasmic SAMD9 immunostaining under basal conditions. No differential expression was observed between SAMD9 or SAMD9L mRNA levels in pACT and in normal pediatric adrenals. Moreover, no association between SAMD9 immunostaining, SAMD9 or SAMD9L mRNA levels, tumor presentation and patient outcome were observed in our cohort, nor in the in silico evaluation. Conclusion: SAMD9 is nuclear and cytoplasmic expressed during adrenal cortex adrenal development and its loss of function is associated with adrenal hypoplasia. On the other hand, SAMD9 is mostly cytoplasmic expressed in pACT and immortalized NCI-H295R cells. No differential expression of SAMD9 nor its counterpart SAMD9L mRNA were associated with tumor presentation and pediatric patient outcome.

Dataset Information

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

Publications

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

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