8qxl

Cryo-EM structure of tetrameric human SAMHD1 State II - Hemi-relaxedCryo-EM structure of tetrameric human SAMHD1 State II - Hemi-relaxed

Structural highlights

8qxl is a 4 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:	Electron Microscopy, Resolution 2.82Å
Ligands:	, , , , , ,
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 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2'-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting T-cells SAMHD1 activity results in the inhibition of HIV-1 infection through a dNTP blockade. In cancer, SAMHD1 desensitizes cells to nucleoside-analogue chemotherapies. Here we employ time-resolved cryogenic-EM imaging and single-particle analysis to visualise assembly, allostery and catalysis by this multi-subunit enzyme. Our observations reveal how dynamic conformational changes in the SAMHD1 quaternary structure drive the catalytic cycle. We capture five states at high-resolution in a live catalytic reaction, revealing how allosteric activators support assembly of a stable SAMHD1 tetrameric core and how catalysis is driven by the opening and closing of active sites through pairwise coupling of active sites and order-disorder transitions in regulatory domains. This direct visualisation of enzyme catalysis dynamics within an allostery-stabilised platform sets a precedent for mechanistic studies into the regulation of multi-subunit enzymes.

Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis.,Acton OJ, Sheppard D, Kunzelmann S, Caswell SJ, Nans A, Burgess AJO, Kelly G, Morris ER, Rosenthal PB, Taylor IA Nat Commun. 2024 May 6;15(1):3775. doi: 10.1038/s41467-024-48237-w. PMID:38710701^[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
↑ Acton OJ, Sheppard D, Kunzelmann S, Caswell SJ, Nans A, Burgess AJO, Kelly G, Morris ER, Rosenthal PB, Taylor IA. Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis. Nat Commun. 2024 May 6;15(1):3775. PMID:38710701 doi:10.1038/s41467-024-48237-w

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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] Acton OJ, Sheppard D, Kunzelmann S, Caswell SJ, Nans A, Burgess AJO, Kelly G, Morris ER, Rosenthal PB, Taylor IA. Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis. Nat Commun. 2024 May 6;15(1):3775. PMID:38710701 doi:10.1038/s41467-024-48237-w

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