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- EMDB-46688: Cryo-EM map of the human UBR4-KCMF1-CaM E3 Ligase complex (Silenc... -

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Basic information

Entry
Database: EMDB / ID: EMD-46688
TitleCryo-EM map of the human UBR4-KCMF1-CaM E3 Ligase complex (Silencing Factor of the Integrated stress response, SiFI) N-terminal region
Map data
Sample
  • Complex: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress response, SiFI)
    • Protein or peptide: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress response, SiFI)
KeywordsE3 ligase / LIGASE / UBR4
Function / homology
Function and homology information


negative regulation of HRI-mediated signaling / ubiquitin-dependent protein catabolic process via the N-end rule pathway / protein K27-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / negative regulation of fatty acid biosynthetic process / endosome organization / cytoplasm protein quality control / protein K11-linked ubiquitination / tertiary granule membrane ...negative regulation of HRI-mediated signaling / ubiquitin-dependent protein catabolic process via the N-end rule pathway / protein K27-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / negative regulation of fatty acid biosynthetic process / endosome organization / cytoplasm protein quality control / protein K11-linked ubiquitination / tertiary granule membrane / ficolin-1-rich granule membrane / protein K48-linked ubiquitination / specific granule membrane / positive regulation of autophagy / RING-type E3 ubiquitin transferase / ubiquitin-protein transferase activity / ubiquitin protein ligase activity / Antigen processing: Ubiquitination & Proteasome degradation / ubiquitin-dependent protein catabolic process / response to oxidative stress / proteasome-mediated ubiquitin-dependent protein catabolic process / calmodulin binding / endosome / protein stabilization / centrosome / Neutrophil degranulation / zinc ion binding / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
E3 ubiquitin-protein ligase UBR4, N-terminal / : / E3 ubiquitin-protein ligase UBR4 N-terminal / UBR4 E3 catalytic module profile. / E3 ubiquitin ligase UBR4, C-terminal / E3 ubiquitin ligase UBR4-like / E3 ubiquitin-protein ligase UBR4 / Putative zinc finger in N-recognin (UBR box) / Zinc finger, UBR-type / Zinc finger UBR-type profile. ...E3 ubiquitin-protein ligase UBR4, N-terminal / : / E3 ubiquitin-protein ligase UBR4 N-terminal / UBR4 E3 catalytic module profile. / E3 ubiquitin ligase UBR4, C-terminal / E3 ubiquitin ligase UBR4-like / E3 ubiquitin-protein ligase UBR4 / Putative zinc finger in N-recognin (UBR box) / Zinc finger, UBR-type / Zinc finger UBR-type profile. / Putative zinc finger in N-recognin, a recognition component of the N-end rule pathway / Armadillo-type fold / WD40-repeat-containing domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase UBR4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsYang Z / Haakonsen DL / Rape M
Funding support United States, 2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
The G. Harold and Leila Y. Mathers Foundation United States
CitationJournal: Nature / Year: 2025
Title: Molecular basis of SIFI activity in the integrated stress response.
Authors: Zhi Yang / Diane L Haakonsen / Michael Heider / Samuel R Witus / Alex Zelter / Tobias Beschauner / Michael J MacCoss / Michael Rapé /
Abstract: Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor ...Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor of the integrated stress response (SIFI), to terminate stress response signalling and ensure cellular homeostasis. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here we combine cryo-electron microscopy analysis of endogenous SIFI with AlphaFold modelling and biochemical studies to report the structural and mechanistic basis of the silencing of the integrated stress response. SIFI detects both stress indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and therefore allows a single enzyme to monitor and, if needed, modulate a complex cellular state.
History
DepositionAug 21, 2024-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateJun 11, 2025-
Current statusJun 11, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46688.png

Downloads & links

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Map

FileDownload / File: emd_46688.map.gz / Format: CCP4 / Size: 536.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 520 pix.
= 432.64 Å		0.83 Å/pix.
x 520 pix.
= 432.64 Å		0.83 Å/pix.
x 520 pix.
= 432.64 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.068
Minimum - Maximum-0.49460143 - 0.80083907
Average (Standard dev.)0.00022355477 (±0.013658538)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions520520520
Spacing520520520
CellA=B=C: 432.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_46688_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_46688_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress...

EntireName: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress response, SiFI)
Components
  • Complex: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress response, SiFI)
    • Protein or peptide: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress response, SiFI)

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Supramolecule #1: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress...

SupramoleculeName: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress response, SiFI)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.27 MDa

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Macromolecule #1: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress...

MacromoleculeName: UBR4-KCMF1-CaM complex (Silencing Factor of the Integrated stress response, SiFI)
type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString: MATSGGEEAA AAAPAPGTPA TGADTTPGWE VAVRPLLSAS YSAFEMKELP QLVASVIESE SEILHHEKQY EPFYSSFVAL STHYITTVCS LIPRNQLQSV AAACKVLIEF SLLRLENPDE ACAVSQKHLI LLIKGLCTGC SRLDRTEIIT FTAMMKSAKL PQTVKTLSDV ...String:
MATSGGEEAA AAAPAPGTPA TGADTTPGWE VAVRPLLSAS YSAFEMKELP QLVASVIESE SEILHHEKQY EPFYSSFVAL STHYITTVCS LIPRNQLQSV AAACKVLIEF SLLRLENPDE ACAVSQKHLI LLIKGLCTGC SRLDRTEIIT FTAMMKSAKL PQTVKTLSDV EDQKELASPV SPELRQKEVQ MNFLNQLTSV FNPRTVASQP ISTQTLVEGE NDEQSSTDQA SAIKTKNVFI AQNVASLQEL GGSEKLLRVC LNLPYFLRYI NRFQDAVLAN SFFIMPATVA DATAVRNGFH SLVIDVTMAL DTLSLPVLEP LNPSRLQDVT VLSLSCLYAG VSVATCMAIL HVGSAQQVRT GSTSSKEDDY ESDAATIVQK CLEIYDMIGQ AISSSRRAGG EHYQNFQLLG AWCLLNSLFL ILNLSPTALA DKGKEKDPLA ALRVRDILSR TKEGVGSPKL GPGKGHQGFG VLSVILANHA IKLLTSLFQD LQVEALHKGW ETDGPPAALS IMAQSTSIQR IQRLIDSVPL MNLLLTLLST SYRKACVLQR QRKGSMSSDA SASTDSNTYY EDDFSSTEED SSQDDDSEPI LGQWFEETIS PSKEKAAPPP PPPPPPLESS PRVKSPSKQA PGEKGNILAS RKDPELFLGL ASNILNFITS SMLNSRNNFI RNYLSVSLSE HHMATLASII KEVDKDGLKG SSDEEFAAAL YHFNHSLVTS DLQSPNLQNT LLQQLGVAPF SEGPWPLYIH PQSLSVLSRL LLIWQHKASA QGDPDVPECL KVWDRFLSTM KQNALQGVVP SETEDLNVEH LQMLLLIFHN FTETGRRAIL SLFVQIIQEL SVNMDAQMRF VPLILARLLL IFDYLLHQYS KAPVYLFEQV QHNLLSPPFG WASGSQDSNS RRATTPLYHG FKEVEENWSK HFSSDAVPHP RFYCVLSPEA SEDDLNRLDS VACDVLFSKL VKYDELYAAL TALLAAGSQL DTVRRKENKN VTALEACALQ YYFLILWRIL GILPPSKTYI NQLSMNSPEM SECDILHTLR WSSRLRISSY VNWIKDHLIK QGMKAEHASS LLELASTTKC SSVKYDVEIV EEYFARQISS FCSIDCTTIL QLHEIPSLQS IYTLDAAISK VQVSLDEHFS KMAAETDPHK SSEITKNLLP ATLQLIDTYA SFTRAYLLQN FNEEGTTEKP SKEKLQGFAA VLAIGSSRCK ANTLGPTLVQ NLPSSVQTVC ESWNNINTNE FPNIGSWRNA FANDTIPSES YISAVQAAHL GTLCSQSLPL AASLKHTLLS LVRLTGDLIV WSDEMNPPQV IRTLLPLLLE SSTESVAEIS SNSLERILGP AESDEFLARV YEKLITGCYN ILANHADPNS GLDESILEEC LQYLEKQLES SQARKAMEEF FSDSGELVQI MMATANENLS AKFCNRVLKF FTKLFQLTEK SPNPSLLHLC GSLAQLACVE PVRLQAWLTR MTTSPPKDSD QLDVIQENRQ LLQLLTTYIV RENSQVGEGV CAVLLGTLTP MATEMLANGD GTGFPELMVV MATLASAGQG AGHLQLHNAA VDWLSRCKKY LSQKNVVEKL NANVMHGKHV MILECTCHIM SYLADVTNAL SQSNGQGPSH LSVDGEERAI EVDSDWVEEL AVEEEDSQAE DSDEDSLCNK LCTFTITQKE FMNQHWYHCH TCKMVDGVGV CTVCAKVCHK DHEISYAKYG SFFCDCGAKE DGSCLALVKR TPSSGMSSTM KESAFQSEPR ISESLVRHAS TSSPADKAKV TISDGKVADE EKPKKSSLCR TVEGCREELQ NQANFSFAPL VLDMLNFLMD AIQTNFQQAS AVGSSSRAQQ ALSELHTVEK AVEMTDQLMV PTLGSQEGAF ENVRMNYSGD QGQTIRQLIS AHVLRRVAMC VLSSPHGRRQ HLAVSHEKGK ITVLQLSALL KQADSSKRKL TLTRLASAPV PFTVLSLTGN PCKEDYLAVC GLKDCHVLTF SSSGSVSDHL VLHPQLATGN FIIKAVWLPG SQTELAIVTA DFVKIYDLCV DALSPTFYFL LPSSKIRDVT FLFNEEGKNI IVIMSSAGYI YTQLMEEASS AQQGPFYVTN VLEINHEDLK DSNSQVAGGG VSVYYSHVLQ MLFFSYCQGK SFAATISRTT LEVLQLFPIN IKSSNGGSKT SPALCQWSEV MNHPGLVCCV QQTTGVPLVV MVKPDTFLIQ EIKTLPAKAK IQDMVAIRHT ACNEQQRTTM ILLCEDGSLR IYMANVENTS YWLQPSLQPS SVISIMKPVR KRKTATITTR TSSQVTFPID FFEHNQQLTD VEFGGNDLLQ VYNAQQIKHR LNSTGMYVAN TKPGGFTIEI SNNNSTMVMT GMRIQIGTQA IERAPSYIEI FGRTMQLNLS RSRWFDFPFT REEALQADKK LNLFIGASVD PAGVTMIDAV KIYGKTKEQF GWPDEPPEEF PSASVSNICP SNLNQSNGTG DSDSAAPTTT SGTVLERLVV SSLEALESCF AVGPIIEKER NKNAAQELAT LLLSLPAPAS VQQQSKSLLA SLHTSRSAYH SHKDQALLSK AVQCLNTSSK EGKDLDPEVF QRLVITARSI AIMRPNNLVH FTESKLPQME TEGMDEGKEP QKQLEGDCCS FITQLVNHFW KLHASKPKNA FLAPACLPGL THIEATVNAL VDIIHGYCTC ELDCINTASK IYMQMLLCPD PAVSFSCKQA LIRVLRPRNK RRHVTLPSSP RSNTPMGDKD DDDDDDADEK MQSSGIPNGG HIRQESQEQS EVDHGDFEMV SESMVLETAE NVNNGNPSPL EALLAGAEGF PPMLDIPPDA DDETMVELAI ALSLQQDQQG SSSSALGLQS LGLSGQAPSS SSLDAGTLSD TTASAPASDD EGSTAATDGS TLRTSPADHG GSVGSESGGS AVDSVAGEHS VSGRSSAYGD ATAEGHPAGP GSVSSSTGAI STTTGHQEGD GSEGEGEGET EGDVHTSNRL HMVRLMLLER LLQTLPQLRN VGGVRAIPYM QVILMLTTDL DGEDEKDKGA LDNLLSQLIA ELGMDKKDVS KKNERSALNE VHLVVMRLLS VFMSRTKSGS KSSICESSSL ISSATAAALL SSGAVDYCLH VLKSLLEYWK SQQNDEEPVA TSQLLKPHTT SSPPDMSPFF LRQYVKGHAA DVFEAYTQLL TEMVLRLPYQ IKKITDTNSR IPPPVFDHSW FYFLSEYLMI QQTPFVRRQV RKLLLFICGS KEKYRQLRDL HTLDSHVRGI KKLLEEQGIF LRASVVTASS GSALQYDTLI SLMEHLKACA EIAAQRTINW QKFCIKDDSV LYFLLQVSFL VDEGVSPVLL QLLSCALCGS KVLAALAASS GSSSASSSSA PVAASSGQAT TQSKSSTKKS KKEEKEKEKD GETSGSQEDQ LCTALVNQLN KFADKETLIQ FLRCFLLESN SSSVRWQAHC LTLHIYRNSS KSQQELLLDL MWSIWPELPA YGRKAAQFVD LLGYFSLKTP QTEKKLKEYS QKAVEILRTQ NHILTNHPNS NIYNTLSGLV EFDGYYLESD PCLVCNNPEV PFCYIKLSSI KVDTRYTTTQ QVVKLIGSHT ISKVTVKIGD LKRTKMVRTI NLYYNNRTVQ AIVELKNKPA RWHKAKKVQL TPGQTEVKID LPLPIVASNL MIEFADFYEN YQASTETLQC PRCSASVPAN PGVCGNCGEN VYQCHKCRSI NYDEKDPFLC NACGFCKYAR FDFMLYAKPC CAVDPIENEE DRKKAVSNIN TLLDKADRVY HQLMGHRPQL ENLLCKVNEA APEKPQDDSG TAGGISSTSA SVNRYILQLA QEYCGDCKNS FDELSKIIQK VFASRKELLE YDLQQREAAT KSSRTSVQPT FTASQYRALS VLGCGHTSST KCYGCASAVT EHCITLLRAL ATNPALRHIL VSQGLIRELF DYNLRRGAAA MREEVRQLMC LLTRDNPEAT QQMNDLIIGK VSTALKGHWA NPDLASSLQY EMLLLTDSIS KEDSCWELRL RCALSLFLMA VNIKTPVVVE NITLMCLRIL QKLIKPPAPT SKKNKDVPVE ALTTVKPYCN EIHAQAQLWL KRDPKASYDA WKKCLPIRGI DGNGKAPSKS ELRHLYLTEK YVWRWKQFLS RRGKRTSPLD LKLGHNNWLR QVLFTPATQA ARQAACTIVE ALATIPSRKQ QVLDLLTSYL DELSIAGECA AEYLALYQKL ITSAHWKVYL AARGVLPYVG NLITKEIARL LALEEATLST DLQQGYALKS LTGLLSSFVE VESIKRHFKS RLVGTVLNGY LCLRKLVVQR TKLIDETQDM LLEMLEDMTT GTESETKAFM AVCIETAKRY NLDDYRTPVF IFERLCSIIY PEENEVTEFF VTLEKDPQQE DFLQGRMPGN PYSSNEPGIG PLMRDIKNKI CQDCDLVALL EDDSGMELLV NNKIISLDLP VAEVYKKVWC TTNEGEPMRI VYRMRGLLGD ATEEFIESLD STTDEEEDEE EVYKMAGVMA QCGGLECMLN RLAGIRDFKQ GRHLLTVLLK LFSYCVKVKV NRQQLVKLEM NTLNVMLGTL NLALVAEQES KDSGGAAVAE QVLSIMEIIL DESNAEPLSE DKGNLLLTGD KDQLVMLLDQ INSTFVRSNP SVLQGLLRII PYLSFGEVEK MQILVERFKP YCNFDKYDED HSGDDKVFLD CFCKIAAGIK NNSNGHQLKD LILQKGITQN ALDYMKKHIP SAKNLDADIW KKFLSRPALP FILRLLRGLA IQHPGTQVLI GTDSIPNLHK LEQVSSDEGI GTLAENLLEA LREHPDVNKK IDAARRETRA EKKRMAMAMR QKALGTLGMT TNEKGQVVTK TALLKQMEEL IEEPGLTCCI CREGYKFQPT KVLGIYTFTK RVALEEMENK PRKQQGYSTV SHFNIVHYDC HLAAVRLARG REEWESAALQ NANTKCNGLL PVWGPHVPES AFATCLARHN TYLQECTGQR EPTYQLNIHD IKLLFLRFAM EQSFSADTGG GGRESNIHLI PYIIHTVLYV LNTTRATSRE EKNLQGFLEQ PKEKWVESAF EVDGPYYFTV LALHILPPEQ WRATRVEILR RLLVTSQARA VAPGGATRLT DKAVKDYSAY RSSLLFWALV DLIYNMFKKV PTSNTEGGWS CSLAEYIRHN DMPIYEAADK ALKTFQEEFM PVETFSEFLD VAGLLSEITD PESFLKDLLN SVP

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 223845
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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