Abstract
Human SAMHD1 (hSAMHD1) is a retroviral restriction factor that blocks HIV-1 infection by depleting the cellular nucleotides required for viral reverse transcription. SAMHD1 is allosterically activated by nucleotides that induce assembly of the active tetramer. Although the catalytic core of hSAMHD1 has been studied extensively, previous structures have not captured the regulatory SAM domain. Here we report the crystal structure of full-length SAMHD1 by capturing mouse SAMHD1 (mSAMHD1) structures in three different nucleotide bound states. Although mSAMHD1 and hSAMHD1 are highly similar in sequence and function, we find that mSAMHD1 possesses a more complex nucleotide-induced activation process, highlighting the regulatory role of the SAM domain. Our results provide insights into the regulation of SAMHD1 activity, thereby facilitating the improvement of HIV mouse models and the development of new therapies for certain cancers and autoimmune diseases.
Highlights
Human SAMHD1 is a retroviral restriction factor that blocks HIV-1 infection by depleting the cellular nucleotides required for viral reverse transcription
To determine whether the sterile alpha-motif (SAM) domain plays a role in the tetramer formation of mSAMHD1, we repeated these assays with truncated proteins that do not contain the SAM domains, namely mouse SAMHD1 HD domain. mHD exists in an equilibrium of monomers and dimers in the absence of allosteric nucleotides (Fig. 1f), similar to what has been observed with human SAMHD1 HD domain[12,15]
We provide a rigorous biochemical analysis and crystal structures of full-length mouse SAMHD1 that capture the interactions between the SAM and HD domains
Summary
Human SAMHD1 (hSAMHD1) is a retroviral restriction factor that blocks HIV-1 infection by depleting the cellular nucleotides required for viral reverse transcription. The effect of phosphorylation of mSAMHD1 iso[1] is still unclear, studies suggest that the T634D phosphomimetic mutation leads to loss of HIV-1 restriction in non-dividing cells, it has no effect on murine leukemia virus infection in dividing cells[18] This suggests that different mechanisms of regulating retroviral restriction exist between hSAMHD1 and mSAMHD1. We explore the structural and functional differences between human and mouse SAMHD1 While both mSAMHD1 and hSAMHD1 are allosterically activated by nucleotides, we find that the two enzymes have different assembly processes for the active tetramers. In addition to capturing important interactions between the SAM and HD domains, these structures delineate the mSAMHD1 allosteric activation process that governs SAMHD1 enzymatic activities These results are important for the assessment of SAMHD1 as a potential therapeutic target for HIV-1 infection and autoimmune diseases, such as AGS
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