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- PDB-7anw: hSARM1 NAD+ complex -

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Basic information

Entry
Database: PDB / ID: 7anw
TitlehSARM1 NAD+ complex
ComponentsNAD(+) hydrolase SARM1
KeywordsAPOPTOSIS / NADase / ARM domain / SAM domain / TIR domain
Function / homology
Function and homology information


negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / nervous system process ...negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / nervous system process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to axon injury / response to glucose / signaling adaptor activity / regulation of neuron apoptotic process / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / nervous system development / microtubule / mitochondrial outer membrane / cell differentiation / axon / innate immune response / dendrite / synapse / signal transduction / mitochondrion / identical protein binding / cytosol / cytoplasm
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
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD(+) hydrolase SARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.68 Å
AuthorsSporny, M. / Guez-Haddad, J. / Khazma, T. / Yaron, A. / Mim, C. / Isupov, M.N. / Zalk, R. / Dessau, M. / Hons, M. / Opatowsky, Y.
Funding support Israel, 1items
OrganizationGrant numberCountry
Israel Science Foundation909/19 Israel
CitationJournal: Elife / Year: 2020
Title: Structural basis for SARM1 inhibition and activation under energetic stress.
Authors: Michael Sporny / Julia Guez-Haddad / Tami Khazma / Avraham Yaron / Moshe Dessau / Yoel Shkolnisky / Carsten Mim / Michail N Isupov / Ran Zalk / Michael Hons / Yarden Opatowsky /
Abstract: SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation ...SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation under stress conditions are still unknown. Here, we present cryo-EM maps of SARM1 at 2.9 and 2.7 Å resolutions. These indicate that SARM1 homo-octamer avoids premature activation by assuming a packed conformation, with ordered inner and peripheral rings, that prevents dimerization and activation of the catalytic domains. This inactive conformation is stabilized by binding of SARM1's own substrate NAD+ in an allosteric location, away from the catalytic sites. This model was validated by mutagenesis of the allosteric site, which led to constitutively active SARM1. We propose that the reduction of cellular NAD+ concentration contributes to the disassembly of SARM1's peripheral ring, which allows formation of active NADase domain dimers, thereby further depleting NAD+ to cause an energetic catastrophe and cell death.
History
DepositionOct 13, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 9, 2020Group: Database references / Category: citation / Item: _citation.title

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Structure visualization

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  • Deposited structure unit
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Structure viewerMolecule:
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Assembly

Deposited unit
A: NAD(+) hydrolase SARM1
B: NAD(+) hydrolase SARM1
C: NAD(+) hydrolase SARM1
D: NAD(+) hydrolase SARM1
E: NAD(+) hydrolase SARM1
F: NAD(+) hydrolase SARM1
G: NAD(+) hydrolase SARM1
H: NAD(+) hydrolase SARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)644,02816
Polymers638,7208
Non-polymers5,3078
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering, doi: 10.1016/j.jmb.2019.06.030. Epub 2019 Jul 3. Structural Evidence for an Octameric Ring Arrangement of SARM1
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area47800 Å2
ΔGint-80 kcal/mol
Surface area205140 Å2
MethodPISA
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14A
24E
15A
25F
16A
26G
17A
27H
18B
28C
19B
29D
110B
210E
111B
211F
112B
212G
113B
213H
114C
214D
115C
215E
116C
216F
117C
217G
118C
218H
119D
219E
120D
220F
121D
221G
122D
222H
123E
223F
124E
224G
125E
225H
126F
226G
127F
227H
128G
228H

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A56 - 700
2010B56 - 700
1020A56 - 700
2020C56 - 700
1030A56 - 700
2030D56 - 700
1040A56 - 700
2040E56 - 700
1050A56 - 700
2050F56 - 700
1060A56 - 700
2060G56 - 700
1070A56 - 700
2070H56 - 700
1080B56 - 700
2080C56 - 700
1090B56 - 700
2090D56 - 700
10100B56 - 700
20100E56 - 700
10110B56 - 700
20110F56 - 700
10120B56 - 700
20120G56 - 700
10130B56 - 700
20130H56 - 700
10140C56 - 700
20140D56 - 700
10150C56 - 700
20150E56 - 700
10160C56 - 700
20160F56 - 700
10170C56 - 700
20170G56 - 700
10180C56 - 700
20180H56 - 700
10190D56 - 700
20190E56 - 700
10200D56 - 700
20200F56 - 700
10210D56 - 700
20210G56 - 700
10220D56 - 700
20220H56 - 700
10230E56 - 700
20230F56 - 700
10240E56 - 700
20240G56 - 700
10250E56 - 700
20250H56 - 700
10260F56 - 700
20260G56 - 700
10270F56 - 700
20270H56 - 700
10280G56 - 700
20280H56 - 700

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28

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Components

#1: Protein
NAD(+) hydrolase SARM1 / hSARM1 / NADP(+) hydrolase SARM1 / Sterile alpha and Armadillo repeat protein / Sterile alpha and ...hSARM1 / NADP(+) hydrolase SARM1 / Sterile alpha and Armadillo repeat protein / Sterile alpha and TIR motif-containing protein 1 / Sterile alpha motif domain-containing protein 2 / SAM domain-containing protein 2 / Tir-1 homolog / HsTIR


Mass: 79840.062 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SARM1, KIAA0524, SAMD2, SARM / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: Q6SZW1, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase, Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds
#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: hSARM1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0258 / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.68 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 159340 / Symmetry type: POINT
RefinementResolution: 2.68→289.45 Å / Cor.coef. Fo:Fc: 0.963 / SU B: 6.057 / SU ML: 0.101 / ESU R: 0.108
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflection
Rwork0.3143 --
obs0.3143 2638191 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 183.035 Å2
Baniso -1Baniso -2Baniso -3
1--0.78 Å20 Å2-0 Å2
2---0.78 Å2-0 Å2
3---1.56 Å2
Refinement stepCycle: 1 / Total: 40520
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.01241232
ELECTRON MICROSCOPYr_bond_other_d
ELECTRON MICROSCOPYr_angle_refined_deg1.7071.6355832
ELECTRON MICROSCOPYr_angle_other_deg
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.03755152
ELECTRON MICROSCOPYr_dihedral_angle_2_deg34.87421.252240
ELECTRON MICROSCOPYr_dihedral_angle_3_deg19.389157296
ELECTRON MICROSCOPYr_dihedral_angle_4_deg20.77615384
ELECTRON MICROSCOPYr_chiral_restr0.1150.25256
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.0231248
ELECTRON MICROSCOPYr_gen_planes_other
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it13.51916.93620632
ELECTRON MICROSCOPYr_mcbond_other
ELECTRON MICROSCOPYr_mcangle_it21.79625.41225776
ELECTRON MICROSCOPYr_mcangle_other
ELECTRON MICROSCOPYr_scbond_it20.13519.0920600
ELECTRON MICROSCOPYr_scbond_other
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other
ELECTRON MICROSCOPYr_long_range_B_refined51.311176032
ELECTRON MICROSCOPYr_long_range_B_other
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: ELECTRON MICROSCOPY / Type: interatomic distance / Rms dev position: 0 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A43778
12B43778
21A43778
22C43778
31A43778
32D43778
41A43778
42E43778
51A43778
52F43778
61A43778
62G43778
71A43778
72H43778
81B43778
82C43778
91B43782
92D43782
101B43778
102E43778
111B43782
112F43782
121B43778
122G43778
131B43780
132H43780
141C43778
142D43778
151C43778
152E43778
161C43778
162F43778
171C43778
172G43778
181C43778
182H43778
191D43778
192E43778
201D43782
202F43782
211D43778
212G43778
221D43780
222H43780
231E43778
232F43778
241E43778
242G43778
251E43778
252H43778
261F43778
262G43778
271F43780
272H43780
281G43778
282H43778
LS refinement shellResolution: 2.68→2.75 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork2.045 195552 -
obs--100 %

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