6brk

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The SAM domain of mouse SAMHD1 is critical for its activation and regulationThe SAM domain of mouse SAMHD1 is critical for its activation and regulation

Structural highlights

6brk is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.5Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SAMH1_MOUSE Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks (By similarity). Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses: dNTPase activity reduces cellular dNTP levels to levels too low for retroviral reverse transcription to occur, blocking early-stage virus replication in dendritic and other myeloid cells (PubMed:23872947, PubMed:23972988, PubMed:26667483, PubMed:29379009, PubMed:31548683). Likewise, suppresses LINE-1 retrotransposon activity (PubMed:26667483). In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools (By similarity). Phosphorylation at Thr-634 acts as a switch to control dNTPase-dependent and -independent functions: it inhibits dNTPase activity and ability to restrict infection by viruses, while it promotes DNA end resection at stalled replication forks (By similarity). Functions during S phase at stalled DNA replication forks to promote the resection of gapped or reversed forks: acts by stimulating the exonuclease activity of MRE11, activating the ATR-CHK1 pathway and allowing the forks to restart replication (By similarity). Its ability to promote degradation of nascent DNA at stalled replication forks is required to prevent induction of type I interferons, thereby preventing chronic inflammation (By similarity). Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity (By similarity). Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation (PubMed:29669924).[UniProtKB:Q9Y3Z3][1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

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.

The SAM domain of mouse SAMHD1 is critical for its activation and regulation.,Buzovetsky O, Tang C, Knecht KM, Antonucci JM, Wu L, Ji X, Xiong Y Nat Commun. 2018 Jan 29;9(1):411. doi: 10.1038/s41467-017-02783-8. PMID:29379009[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Rehwinkel J, Maelfait J, Bridgeman A, Rigby R, Hayward B, Liberatore RA, Bieniasz PD, Towers GJ, Moita LF, Crow YJ, Bonthron DT, Reis e Sousa C. SAMHD1-dependent retroviral control and escape in mice. EMBO J. 2013 Sep 11;32(18):2454-62. PMID:23872947 doi:10.1038/emboj.2013.163
  2. ↑ Behrendt R, Schumann T, Gerbaulet A, Nguyen LA, Schubert N, Alexopoulou D, Berka U, Lienenklaus S, Peschke K, Gibbert K, Wittmann S, Lindemann D, Weiss S, Dahl A, Naumann R, Dittmer U, Kim B, Mueller W, Gramberg T, Roers A. Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response. Cell Rep. 2013 Aug 29;4(4):689-96. PMID:23972988 doi:10.1016/j.celrep.2013.07.037
  3. ↑ Wittmann S, Behrendt R, Eissmann K, Volkmann B, Thomas D, Ebert T, Cribier A, Benkirane M, Hornung V, Bouzas NF, Gramberg T. Phosphorylation of murine SAMHD1 regulates its antiretroviral activity. Retrovirology. 2015 Dec 15;12:103. PMID:26667483 doi:10.1186/s12977-015-0229-6
  4. ↑ Buzovetsky O, Tang C, Knecht KM, Antonucci JM, Wu L, Ji X, Xiong Y. The SAM domain of mouse SAMHD1 is critical for its activation and regulation. Nat Commun. 2018 Jan 29;9(1):411. doi: 10.1038/s41467-017-02783-8. PMID:29379009 doi:http://dx.doi.org/10.1038/s41467-017-02783-8
  5. ↑ Thientosapol ES, Bosnjak D, Durack T, Stevanovski I, van Geldermalsen M, Holst J, Jahan Z, Shepard C, Weninger W, Kim B, Brink R, Jolly CJ. SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation. Proc Natl Acad Sci U S A. 2018 May 8;115(19):4921-4926. PMID:29669924 doi:10.1073/pnas.1719771115
  6. ↑ Deutschmann J, Schneider A, Gruska I, Vetter B, Thomas D, Kießling M, Wittmann S, Herrmann A, Schindler M, Milbradt J, Ferreirós N, Winkler TH, Wiebusch L, Gramberg T. A viral kinase counteracts in vivo restriction of murine cytomegalovirus by SAMHD1. Nat Microbiol. 2019 Dec;4(12):2273-2284. PMID:31548683 doi:10.1038/s41564-019-0529-z
  7. ↑ Buzovetsky O, Tang C, Knecht KM, Antonucci JM, Wu L, Ji X, Xiong Y. The SAM domain of mouse SAMHD1 is critical for its activation and regulation. Nat Commun. 2018 Jan 29;9(1):411. doi: 10.1038/s41467-017-02783-8. PMID:29379009 doi:http://dx.doi.org/10.1038/s41467-017-02783-8

6brk, resolution 3.50Å

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