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- PDB-7lcy: Crystal structure of the ligand-free ARM domain from Drosophila SARM1 -

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Basic information

Entry
Database: PDB / ID: 7lcy
TitleCrystal structure of the ligand-free ARM domain from Drosophila SARM1
ComponentsIsoform B of NAD(+) hydrolase sarm1
KeywordsHYDROLASE / NADase / Autoinhibition / ARM domain / Allostery / SIGNALING PROTEIN
Function / homology
Function and homology information


negative regulation of MyD88-independent toll-like receptor signaling pathway / positive regulation of receptor signaling pathway via STAT / NAD catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity / NAD+ nucleotidase, cyclic ADP-ribose generating / STAT family protein binding / antiviral innate immune response / response to axon injury / signaling adaptor activity ...negative regulation of MyD88-independent toll-like receptor signaling pathway / positive regulation of receptor signaling pathway via STAT / NAD catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity / NAD+ nucleotidase, cyclic ADP-ribose generating / STAT family protein binding / antiviral innate immune response / response to axon injury / signaling adaptor activity / defense response to virus / neuron projection / axon / neuronal cell body / dendrite / signal transduction / cytosol
Similarity search - Function
Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain ...Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
NAD(+) hydrolase sarm1
Similarity search - Component
Biological speciesDrosophila melanogaster (fruit fly)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.35 Å
AuthorsGu, W. / Nanson, J.D. / Luo, Z. / McGuinness, H.Y. / Manik, M.K. / Jia, X. / Ve, T. / Kobe, B.
Funding support Australia, 6items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1107804 Australia
National Health and Medical Research Council (NHMRC, Australia)1160570 Australia
National Health and Medical Research Council (NHMRC, Australia)1071659 Australia
National Health and Medical Research Council (NHMRC, Australia)1108859 Australia
Australian Research Council (ARC)FL180100109 Australia
Australian Research Council (ARC)DE170100783 Australia
CitationJournal: Neuron / Year: 2021
Title: SARM1 is a metabolic sensor activated by an increased NMN/NAD ratio to trigger axon degeneration.
Authors: Matthew D Figley / Weixi Gu / Jeffrey D Nanson / Yun Shi / Yo Sasaki / Katie Cunnea / Alpeshkumar K Malde / Xinying Jia / Zhenyao Luo / Forhad K Saikot / Tamim Mosaiab / Veronika Masic / ...Authors: Matthew D Figley / Weixi Gu / Jeffrey D Nanson / Yun Shi / Yo Sasaki / Katie Cunnea / Alpeshkumar K Malde / Xinying Jia / Zhenyao Luo / Forhad K Saikot / Tamim Mosaiab / Veronika Masic / Stephanie Holt / Lauren Hartley-Tassell / Helen Y McGuinness / Mohammad K Manik / Todd Bosanac / Michael J Landsberg / Philip S Kerry / Mehdi Mobli / Robert O Hughes / Jeffrey Milbrandt / Bostjan Kobe / Aaron DiAntonio / Thomas Ve /
Abstract: Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide ...Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD ratio by cleaving residual NAD, thereby inducing feedforward metabolic catastrophe and axonal demise.
History
DepositionJan 12, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 17, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 21, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform B of NAD(+) hydrolase sarm1
B: Isoform B of NAD(+) hydrolase sarm1
C: Isoform B of NAD(+) hydrolase sarm1


Theoretical massNumber of molelcules
Total (without water)121,2303
Polymers121,2303
Non-polymers00
Water00
1
A: Isoform B of NAD(+) hydrolase sarm1


Theoretical massNumber of molelcules
Total (without water)40,4101
Polymers40,4101
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Isoform B of NAD(+) hydrolase sarm1


Theoretical massNumber of molelcules
Total (without water)40,4101
Polymers40,4101
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Isoform B of NAD(+) hydrolase sarm1


Theoretical massNumber of molelcules
Total (without water)40,4101
Polymers40,4101
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.301, 101.363, 98.574
Angle α, β, γ (deg.)90.000, 103.769, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Isoform B of NAD(+) hydrolase sarm1 / NADase sarm1 / Sterile alpha and TIR motif-containing protein 1 / Tir-1 homolog


Mass: 40409.895 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Drosophila melanogaster (fruit fly) / Gene: Sarm, Ect4, CG43119 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q6IDD9, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.53 Å3/Da / Density % sol: 51.45 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 1.7 M sodium malonate pH 5.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 3.35→47.87 Å / Num. obs: 17198 / % possible obs: 97.7 % / Redundancy: 3.4 % / Biso Wilson estimate: 86.43 Å2 / CC1/2: 0.996 / Net I/σ(I): 4.7
Reflection shellResolution: 3.35→3.85 Å / Num. unique obs: 3286 / CC1/2: 0.373

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
PHASERphasing
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.35→47.87 Å / SU ML: 0.4916 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.5397 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.2717 791 4.61 %
Rwork0.2445 16356 -
obs0.2458 17147 98.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 90.85 Å2
Refinement stepCycle: LAST / Resolution: 3.35→47.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7424 0 0 0 7424
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00157545
X-RAY DIFFRACTIONf_angle_d0.437410190
X-RAY DIFFRACTIONf_chiral_restr0.03341171
X-RAY DIFFRACTIONf_plane_restr0.00251319
X-RAY DIFFRACTIONf_dihedral_angle_d13.85372780
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.35-3.560.38741070.33342536X-RAY DIFFRACTION91.74
3.56-3.840.32381350.29562757X-RAY DIFFRACTION99.62
3.84-4.220.29481530.26022756X-RAY DIFFRACTION99.69
4.22-4.830.28571260.22342767X-RAY DIFFRACTION99.69
4.83-6.090.28841390.25982758X-RAY DIFFRACTION99.79
6.09-47.870.20261310.19862782X-RAY DIFFRACTION98.01
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
17.632012918960.3578872076580.8308470792528.764990177326.350552745646.18517190543-0.2288553559980.2404041950560.316402542359-0.2694947942690.009890393864670.941937911976-0.875024320323-0.05542760820680.1251539293840.835972455594-0.06082585302550.07759535551830.4919423602280.1137319215370.7275112090917.503842705721.12659051950.892214644608
24.822499618310.9425592000711.467509971144.66394308185-5.257309116658.094004356610.582073134082-0.542786934886-0.07298725199332.31143368819-0.2097689838710.798918093441.477044831390.243744710377-0.2262239323811.42432738688-0.1881566380150.361008511760.6068275763990.02217408687230.92979019551623.111461901614.439446543615.0541891616
34.054865688770.92539260951-0.6845962749594.38250898333-0.5683262407634.880107087340.235106748518-0.1638456481180.1719564429840.430626575303-0.212172218398-0.123750651306-0.2726065924090.0264026413671-0.03954357836090.8123694485280.001418458797370.1175254550360.4145684646220.0116340874480.49959363289928.1189565556-2.212330469016.1971176888
45.06831523050.7371253154111.552200787814.83403425436-5.060013944477.86803774605-0.2181151646650.192666012423-0.576781896479-0.287099716662-0.212374525306-0.5659768399380.4597098511760.37408147770.3919702917620.593797972296-0.02174319148180.1380081631070.393001851235-0.05871039017240.4985851987431.7555900761-4.42723633438-14.298772761
52.235525083442.23254592079-1.522294068743.23972569245-2.276773500228.906650094420.225935813295-0.4951645098690.391664281228-0.0927159810785-0.617871276046-0.7935029148511.084867096660.7577093815080.3660552401430.6600409176110.0477094506887-0.1259114857780.849702319842-0.03794125667361.1643768646728.8208369067-23.364049169943.3732335345
610.06587784753.26824954597-5.014773039535.78693878383-4.663634032662.18737954105-1.010960957920.121085152022-0.307946262884-0.0409843369210.189103826107-0.4745578899050.8954327259330.7316011918221.056156910210.5859430913880.1015869011660.05444190681740.864776929548-0.1021088216530.75379933927219.6275608597-26.712239580742.2446294557
73.302127925280.3421926905991.228198559546.79851102113-2.882806372957.11635058038-0.221360695644-0.00210246048101-0.454811971405-0.199349335490.238694769943-0.3876499049630.611087971436-0.163884016296-0.01911743395430.591351016961-0.08412515245730.2142966274850.510337221775-0.07844643598190.547023811836.24126419443-22.607423117937.1284714738
84.505714090892.090122024360.352335256512.69904089588-0.9773925255071.200689574730.152797251103-0.7398944122770.3210364672170.410961095835-0.3578419396450.8304379396350.195031078297-0.4901752283530.3061254530141.20846951904-0.0462809758910.3139101771710.924499051828-0.1597397585470.724237268349-2.68655396248-16.455678695726.8509418478
92.44296181289-0.701271306035-4.085109964472.443769874590.4685394189096.21795276357-0.1911890886230.656027162102-0.129060536308-0.737829050490.05373309489380.04292559588190.24706297393-0.6688540477150.1451850592431.01041945306-0.07525239001820.1339217390930.661754737090.001753010458090.600395087245.21619183803-16.142125102116.5942604312
105.880422139923.57955409165-1.509491879269.802818379272.583897935739.31964569028-0.6795473262040.460669001021-1.09999209856-0.275880371765-0.177005138759-0.003273101322320.494908091109-1.619698328070.6873671848490.87483883695-0.1235803038130.2741140283530.753043170069-0.08524101470350.56730121636612.0205930038-21.55101237166.74154407029
111.08391000378-1.73532083689-0.7130599998945.74738278543.490860126952.24196764655-0.0586825268892-0.0884572566285-0.404552750185-0.253910408902-0.3184399925950.229626597776-0.328138547505-1.119862614210.1076872658410.739854829073-0.00138719119233-0.1975733830771.024870518750.1179392643771.06834151128-2.75855130847-15.7987070351-33.1009164041
125.73238385201-0.955463245142-1.095576814144.9543194004-0.07970071687427.17873587675-0.02550344037010.0332154897758-0.169118634004-0.2582890641790.2220922353670.136160200039-0.320957762334-0.814158569543-0.1781819688440.596993197820.02249576571120.06111621135130.516068416584-0.01716173729290.44721863240812.89891299363.04642235124-31.6728731297
138.752187588711.185281209394.050922449914.614756250142.772543740876.22611393472-0.09507082026231.70230321175-0.732572877389-0.3569570615930.475641957058-0.3208671429450.2782505781440.179937260257-0.1074038562320.976551882426-0.08235433907120.2913929491810.711917546175-0.2212345188790.71799360159824.4078185759-3.88749980894-46.356801648
148.03439124735-2.301041352832.012574344466.654866171032.138892715286.677981908590.2006568028421.179830038510.186292605398-0.539455709717-0.252924137508-0.136472393484-1.21400438063-0.297001384260.0303855569930.964450379770.1031434384340.2213944886190.8148642536720.05243384103870.44193737526817.0419016872.64436522751-54.9647601589
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 326 through 404 )
2X-RAY DIFFRACTION2chain 'A' and (resid 405 through 430 )
3X-RAY DIFFRACTION3chain 'A' and (resid 431 through 559 )
4X-RAY DIFFRACTION4chain 'A' and (resid 560 through 676 )
5X-RAY DIFFRACTION5chain 'B' and (resid 339 through 391 )
6X-RAY DIFFRACTION6chain 'B' and (resid 392 through 433 )
7X-RAY DIFFRACTION7chain 'B' and (resid 434 through 520 )
8X-RAY DIFFRACTION8chain 'B' and (resid 521 through 561 )
9X-RAY DIFFRACTION9chain 'B' and (resid 562 through 637 )
10X-RAY DIFFRACTION10chain 'B' and (resid 638 through 676 )
11X-RAY DIFFRACTION11chain 'C' and (resid 333 through 420 )
12X-RAY DIFFRACTION12chain 'C' and (resid 421 through 574 )
13X-RAY DIFFRACTION13chain 'C' and (resid 575 through 602 )
14X-RAY DIFFRACTION14chain 'C' and (resid 603 through 675 )

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