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- PDB-7zvj: Homodimeric structure of LARGE1 -

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Basic information

Entry
Database: PDB / ID: 7zvj
TitleHomodimeric structure of LARGE1
ComponentsXylosyl- and glucuronyltransferase LARGE1
KeywordsTRANSFERASE / matriglycan / xylose / glucuronic acid / polymerase / TRANSFERASE.
Function / homology
Function and homology information


post-embryonic hindlimb morphogenesis / Defective LARGE causes MDDGA6 and MDDGB6 / xylosyltransferase activity / principal sensory nucleus of trigeminal nerve development / walking behavior / connective tissue development / glycosphingolipid biosynthetic process / skeletal muscle organ development / glucuronosyltransferase activity / Matriglycan biosynthesis on DAG1 ...post-embryonic hindlimb morphogenesis / Defective LARGE causes MDDGA6 and MDDGB6 / xylosyltransferase activity / principal sensory nucleus of trigeminal nerve development / walking behavior / connective tissue development / glycosphingolipid biosynthetic process / skeletal muscle organ development / glucuronosyltransferase activity / Matriglycan biosynthesis on DAG1 / Transferases; Glycosyltransferases / UDP-xylosyltransferase activity / localization of cell / synaptic assembly at neuromuscular junction / negative regulation of muscle cell apoptotic process / protein O-linked glycosylation via mannose / N-acetylglucosamine metabolic process / neuromuscular process controlling posture / acetylglucosaminyltransferase activity / retina layer formation / skeletal muscle fiber differentiation / plasma membrane organization / retina vasculature development in camera-type eye / reactive gliosis / basement membrane organization / hexosyltransferase activity / nerve development / water transport / positive regulation of skeletal muscle acetylcholine-gated channel clustering / glycoprotein biosynthetic process / neuromuscular synaptic transmission / protein O-linked glycosylation / dentate gyrus development / skeletal muscle tissue regeneration / astrocyte differentiation / acetylcholine receptor signaling pathway / cardiac muscle cell development / protein targeting to membrane / Transferases; Glycosyltransferases; Hexosyltransferases / muscle cell cellular homeostasis / blood vessel development / glycosyltransferase activity / macrophage differentiation / Transferases; Glycosyltransferases; Pentosyltransferases / response to light stimulus / response to mechanical stimulus / positive regulation of Rac protein signal transduction / behavioral fear response / striated muscle contraction / skeletal muscle fiber development / myelination / cytoskeleton organization / post-translational protein modification / potassium ion transmembrane transport / determination of adult lifespan / protein localization to plasma membrane / neuromuscular junction / sensory perception of sound / intracellular protein transport / bone development / multicellular organism growth / neuron migration / memory / long-term synaptic potentiation / manganese ion binding / protein-containing complex assembly / gene expression / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Golgi membrane / Golgi apparatus / protein-containing complex / plasma membrane
Similarity search - Function
: / Glycosyl-transferase for dystroglycan / Glycosyl transferase, family 8 / Glycosyl transferase family 8 / Spore Coat Polysaccharide Biosynthesis Protein SpsA; Chain A / Spore Coat Polysaccharide Biosynthesis Protein SpsA; Chain A / Nucleotide-diphospho-sugar transferases / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
: / PHOSPHATE ION / Xylosyl- and glucuronyltransferase LARGE1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsDiskin, R. / Katz, M.
Funding support Israel, 1items
OrganizationGrant numberCountry
Not funded Israel
CitationJournal: PLoS One / Year: 2022
Title: Structural basis for matriglycan synthesis by the LARGE1 dual glycosyltransferase.
Authors: Michael Katz / Ron Diskin /
Abstract: LARGE1 is a bifunctional glycosyltransferase responsible for generating a long linear polysaccharide termed matriglycan that links the cytoskeleton and the extracellular matrix and is required for ...LARGE1 is a bifunctional glycosyltransferase responsible for generating a long linear polysaccharide termed matriglycan that links the cytoskeleton and the extracellular matrix and is required for proper muscle function. This matriglycan polymer is made with an alternating pattern of xylose and glucuronic acid monomers. Mutations in the LARGE1 gene have been shown to cause life-threatening dystroglycanopathies through the inhibition of matriglycan synthesis. Despite its major role in muscle maintenance, the structure of the LARGE1 enzyme and how it assembles in the Golgi are unknown. Here we present the structure of LARGE1, obtained by a combination of X-ray crystallography and single-particle cryo-EM. We found that LARGE1 homo-dimerizes in a configuration that is dictated by its coiled-coil stem domain. The structure shows that this enzyme has two canonical GT-A folds within each of its catalytic domains. In the context of its dimeric structure, the two types of catalytic domains are brought into close proximity from opposing monomers to allow efficient shuttling of the substrates between the two domains. Together, with putative retention of matriglycan by electrostatic interactions, this dimeric organization offers a possible mechanism for the ability of LARGE1 to synthesize long matriglycan chains. The structural information further reveals the mechanisms in which disease-causing mutations disrupt the activity of LARGE1. Collectively, these data shed light on how matriglycan is synthesized alongside the functional significance of glycosyltransferase oligomerization.
History
DepositionMay 16, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Xylosyl- and glucuronyltransferase LARGE1
B: Xylosyl- and glucuronyltransferase LARGE1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,7779
Polymers145,9402
Non-polymers8377
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4140 Å2
ΔGint-35 kcal/mol
Surface area50890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)196.531, 107.377, 100.334
Angle α, β, γ (deg.)90.000, 120.260, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11B-803-

PO4

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
d_1ens_1(chain "A" and (resid 134 through 279 or resid 287...
d_2ens_1(chain "B" and (resid 134 through 625 or resid 637 through 712 or resid 720 through 792))

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1LYSGLYA1 - 146
d_12ens_1PROLEUA149 - 222
d_13ens_1GLNPHEA224 - 545
d_14ens_1ASNALAA551 - 583
d_15ens_1NAGNAGB
d_21ens_1LYSPHEC1 - 466
d_22ens_1THRPHEC478 - 553
d_23ens_1ASNALAC555 - 587
d_24ens_1NAGNAGD

NCS oper: (Code: givenMatrix: (0.538872024267, -0.00217157415814, 0.842384844194), (0.010962075718, -0.999893926441, -0.00959003453056), (0.842316314907, 0.014402087766, -0.538791059233)Vector: 0. ...NCS oper: (Code: given
Matrix: (0.538872024267, -0.00217157415814, 0.842384844194), (0.010962075718, -0.999893926441, -0.00959003453056), (0.842316314907, 0.014402087766, -0.538791059233)
Vector: 0.784306295188, -29.7513861862, 4.44067240149)

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Components

#1: Protein Xylosyl- and glucuronyltransferase LARGE1 / Acetylglucosaminyltransferase-like 1A / Glycosyltransferase-like protein / LARGE xylosyl- and ...Acetylglucosaminyltransferase-like 1A / Glycosyltransferase-like protein / LARGE xylosyl- and glucuronyltransferase 1


Mass: 72969.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LARGE1, KIAA0609, LARGE / Production host: Homo sapiens (human)
References: UniProt: O95461, Transferases; Glycosyltransferases, Transferases; Glycosyltransferases; Pentosyltransferases, Transferases; Glycosyltransferases; Hexosyltransferases
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 2.91 Å3/Da / Density % sol: 57.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 1.0 M Na3PO4 monobasic monohydrate, K3PO4 dibasic / pH 5.0 20% PEG 200 as cryo preservative

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Feb 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 2.61→45.64 Å / Num. obs: 52821 / % possible obs: 96 % / Redundancy: 2.7 % / Biso Wilson estimate: 58.09 Å2 / CC1/2: 0.983 / Net I/σ(I): 4.5
Reflection shellResolution: 2.61→2.69 Å / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4425 / CC1/2: 0.149 / % possible all: 93

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: EMD-14985

Resolution: 2.61→45.64 Å / SU ML: 0.5557 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 34.7979
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2703 1194 2.28 %
Rwork0.2146 51217 -
obs0.2159 52411 95.07 %
Solvent computationShrinkage radii: 1 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 84.02 Å2
Refinement stepCycle: LAST / Resolution: 2.61→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9685 0 45 44 9774
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0089979
X-RAY DIFFRACTIONf_angle_d1.219813524
X-RAY DIFFRACTIONf_chiral_restr0.06461476
X-RAY DIFFRACTIONf_plane_restr0.01811694
X-RAY DIFFRACTIONf_dihedral_angle_d6.16961297
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 1.3231410298 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.61-2.710.45421190.40155274X-RAY DIFFRACTION88.69
2.71-2.830.37791360.35595789X-RAY DIFFRACTION97.08
2.83-2.980.33521370.31175828X-RAY DIFFRACTION97.82
2.98-3.170.36151350.30325791X-RAY DIFFRACTION97.32
3.17-3.410.3371360.25285805X-RAY DIFFRACTION97.09
3.41-3.760.31951340.20945759X-RAY DIFFRACTION96.4
3.76-4.30.22111330.17485679X-RAY DIFFRACTION94.46
4.3-5.420.19871300.16675560X-RAY DIFFRACTION92.93
5.42-45.640.25061340.19695732X-RAY DIFFRACTION93.87
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)
11.814753387950.02957201637760.6692310851462.221860648380.177240183461.34342358264-0.09234172783980.188339504877-0.121968746063-0.1835481328180.1204262063160.1860270759540.153127271687-0.19337549364-1.68090548982E-90.53675150997-0.124906688003-0.07086927650530.575338464643-0.0052860226650.4172710802417.1333599116-39.103135184118.0705813128
20.01308929158310.9890238249691.025557552590.8746687142140.2936498784791.15395537445-0.1953976043340.07988440341530.00463741354232-0.2646101504650.03727608944560.0183232124034-0.1847010830490.157010159465-2.10392630292E-60.544645817794-0.01442905153340.01073062430920.555159471994-0.004877309772490.62159297660234.8412338333-22.836300925832.8086581423
32.057923405370.19467029655-0.2378154184820.852403470515-0.2362150954481.27540373920.056704978804-0.01066745292870.01667273527050.11126082172-0.04479606728140.0492364876462-0.2284303940630.09525011581251.00079789058E-100.519739324261-0.0404917846195-0.02486793738720.572329955362-0.01495983177870.56334983655948.5960531783-22.049545900852.9068588206
41.73064542143-0.2411211323420.5983595655640.279088333602-0.6830058991781.13553824290.1555887462340.457147910323-0.109461809120.0695703851129-0.126831674743-0.0821904697007-0.0386639478889-0.1138519358146.59596883349E-100.6319091029590.04973273704320.08765787224450.6896652668030.005938700383170.69681360698934.90526824293.586926938086.76979521094
52.29227049430.3512352473430.02523305409440.760101634963-0.3329943700931.233606434470.2289265461560.3782040019920.28594149796-0.139828754602-0.1424620589980.159387408908-0.0673267197288-0.2265812616982.54729004188E-80.680256242720.07367321564730.04823929354940.7095290763220.07909526212170.74655713218920.625504211513.99318704488.01957415817
60.6007658658210.1357011320310.06033591374250.4821779310590.1863340316480.1912072108520.0908959102957-0.0848518878223-0.5548325913970.3220668731290.04687615738440.16509667953-0.0605522822354-0.249597609165-5.3223799307E-70.8065010552390.007145017322050.1198626832490.7786167653690.1816250510.9076452106519.93401752140.88220285208319.6847870864
71.95633250644-0.3863820192540.5580909404560.761184069568-0.4998322997470.8285637679110.0742482813777-0.199517090138-0.264053144994-0.121179041651-0.09873999260490.300001129375-0.149069242549-0.0993945042047-7.66262407106E-90.7477012201840.01915421262920.02009032370610.5893108443710.01774155628630.61035180124750.6065712286-7.0931889804914.5520481747
81.51979440583-0.309511893832-0.05363989090470.857519999612-0.09155820745951.89956995840.0856311688727-0.00813118331507-0.183890343592-0.162574430258-0.13657019152-0.1610886518460.1232696282550.3152529094441.57890747281E-90.7442410154660.08056996544140.03993280652430.7117092533710.04772844562460.60890072822372.7164966785-5.5501672322719.2809451284
90.389744938049-0.135318459619-0.2395228783340.745149817962-0.02602185627010.262296545724-0.054780569080.0749428801416-0.0984001965803-0.2723246956970.2181099162750.4271749126740.0795385074318-0.4411318557770.398309002151.089433508390.0006653137793780.1318963120940.658984614338-0.03216688161080.75444505313770.7250266395-21.33445929562.93116408337
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 134 through 377 )AA134 - 3771 - 230
22chain 'A' and (resid 378 through 542 )AA378 - 542231 - 386
33chain 'A' and (resid 543 through 752 )AA543 - 752387 - 583
44chain 'B' and (resid 134 through 215 )BC134 - 2151 - 82
55chain 'B' and (resid 216 through 344 )BC216 - 34483 - 204
66chain 'B' and (resid 345 through 405 )BC345 - 405205 - 246
77chain 'B' and (resid 406 through 542 )BC406 - 542247 - 383
88chain 'B' and (resid 543 through 720 )BC543 - 720384 - 555
99chain 'B' and (resid 721 through 752 )BC721 - 752556 - 587

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