4mz7

Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

Structural highlights

4mz7 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	DGT, DTP, MG, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SAMH1_HUMAN Defects in SAMHD1 are the cause of Aicardi-Goutieres syndrome type 5 (AGS5) [MIM:612952. A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.^[1] ^[2] Defects in SAMHD1 are the cause of chilblain lupus type 2 (CHBL2) [MIM:614415. A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade.^[3]

Function

SAMH1_HUMAN Putative nuclease involved in innate immune response by acting as a negative regulator of the cell-intrinsic antiviral response. May play a role in mediating proinflammatory responses to TNF-alpha signaling.^[4] ^[5]

Publication Abstract from PubMed

SAMHD1 is a dGTP-activated deoxynucleoside triphosphate triphosphohydrolase (dNTPase) whose dNTPase activity has been linked to HIV/SIV restriction. The mechanism of its dGTP-activated dNTPase function remains unclear. Recent data also indicate that SAMHD1 regulates retrotransposition of LINE-1 elements. Here we report the 1.8-A crystal structure of homotetrameric SAMHD1 in complex with the allosteric activator and substrate dGTP/dATP. The structure indicates the mechanism of dGTP-dependent tetramer formation, which requires the cooperation of three subunits and two dGTP/dATP molecules at each allosteric site. Allosteric dGTP binding induces conformational changes at the active site, allowing a more stable interaction with the substrate and explaining the dGTP-induced SAMHD1 dNTPase activity. Mutations of dGTP binding residues in the allosteric site affect tetramer formation, dNTPase activity and HIV-1 restriction. dGTP-triggered tetramer formation is also important for SAMHD1-mediated LINE-1 regulation. The structural and functional information provided here should facilitate future investigation of SAMHD1 function, including dNTPase activity, LINE-1 modulation and HIV-1 restriction.

Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase.,Zhu C, Gao W, Zhao K, Qin X, Zhang Y, Peng X, Zhang L, Dong Y, Zhang W, Li P, Wei W, Gong Y, Yu XF Nat Commun. 2013 Nov 12;4:2722. doi: 10.1038/ncomms3722. PMID:24217394^[6]

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

References

↑ Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009 Jul;41(7):829-32. doi: 10.1038/ng.373. Epub 2009 Jun 14. PMID:19525956 doi:10.1038/ng.373
↑ Thiele H, du Moulin M, Barczyk K, George C, Schwindt W, Nurnberg G, Frosch M, Kurlemann G, Roth J, Nurnberg P, Rutsch F. Cerebral arterial stenoses and stroke: novel features of Aicardi-Goutieres syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression. Hum Mutat. 2010 Nov;31(11):E1836-50. doi: 10.1002/humu.21357. PMID:20842748 doi:10.1002/humu.21357
↑ Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A. 2011 Jan;155A(1):235-7. doi: 10.1002/ajmg.a.33778. PMID:21204240 doi:10.1002/ajmg.a.33778
↑ Liao W, Bao Z, Cheng C, Mok YK, Wong WS. Dendritic cell-derived interferon-gamma-induced protein mediates tumor necrosis factor-alpha stimulation of human lung fibroblasts. Proteomics. 2008 Jul;8(13):2640-50. doi: 10.1002/pmic.200700954. PMID:18546154 doi:10.1002/pmic.200700954
↑ Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009 Jul;41(7):829-32. doi: 10.1038/ng.373. Epub 2009 Jun 14. PMID:19525956 doi:10.1038/ng.373
↑ Zhu C, Gao W, Zhao K, Qin X, Zhang Y, Peng X, Zhang L, Dong Y, Zhang W, Li P, Wei W, Gong Y, Yu XF. Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase. Nat Commun. 2013 Nov 12;4:2722. doi: 10.1038/ncomms3722. PMID:24217394 doi:https://dx.doi.org/10.1038/ncomms3722

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OCA

[1] Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009 Jul;41(7):829-32. doi: 10.1038/ng.373. Epub 2009 Jun 14. PMID:19525956 doi:10.1038/ng.373

[2] Thiele H, du Moulin M, Barczyk K, George C, Schwindt W, Nurnberg G, Frosch M, Kurlemann G, Roth J, Nurnberg P, Rutsch F. Cerebral arterial stenoses and stroke: novel features of Aicardi-Goutieres syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression. Hum Mutat. 2010 Nov;31(11):E1836-50. doi: 10.1002/humu.21357. PMID:20842748 doi:10.1002/humu.21357

[3] Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A. 2011 Jan;155A(1):235-7. doi: 10.1002/ajmg.a.33778. PMID:21204240 doi:10.1002/ajmg.a.33778

[4] Liao W, Bao Z, Cheng C, Mok YK, Wong WS. Dendritic cell-derived interferon-gamma-induced protein mediates tumor necrosis factor-alpha stimulation of human lung fibroblasts. Proteomics. 2008 Jul;8(13):2640-50. doi: 10.1002/pmic.200700954. PMID:18546154 doi:10.1002/pmic.200700954

[5] Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009 Jul;41(7):829-32. doi: 10.1038/ng.373. Epub 2009 Jun 14. PMID:19525956 doi:10.1038/ng.373

[6] Zhu C, Gao W, Zhao K, Qin X, Zhang Y, Peng X, Zhang L, Dong Y, Zhang W, Li P, Wei W, Gong Y, Yu XF. Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase. Nat Commun. 2013 Nov 12;4:2722. doi: 10.1038/ncomms3722. PMID:24217394 doi:https://dx.doi.org/10.1038/ncomms3722

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4mz7

Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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