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Protein

Guanine nucleotide exchange protein SMCR8

Gene

SMCR8

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:20562859, PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:20562859, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and inhibiting its protein kinase activity (PubMed:27617292, PubMed:28195531). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131, PubMed:28195531). In addition to its activity in the cytoplasm within the C9orf72-SMCR8 complex, SMCR8 also localizes in the nucleus, where it associates with chromatin and negatively regulates expression of suppresses ULK1 and WIPI2 genes (PubMed:28195531).6 Publications

GO - Molecular functioni

  • guanyl-nucleotide exchange factor activity Source: UniProtKB-KW
  • protein kinase binding Source: UniProtKB
  • protein kinase inhibitor activity Source: HGNC

GO - Biological processi

  • autophagy Source: UniProtKB-KW
  • negative regulation of autophagosome assembly Source: HGNC
  • negative regulation of gene expression Source: HGNC
  • negative regulation of macroautophagy Source: HGNC
  • negative regulation of protein kinase activity Source: HGNC
  • positive regulation of autophagosome maturation Source: HGNC
  • positive regulation of TOR signaling Source: HGNC
  • regulation of autophagy Source: UniProtKB
  • regulation of TORC1 signaling Source: UniProtKB
  • regulation of transcription, DNA-templated Source: UniProtKB-KW
  • transcription, DNA-templated Source: UniProtKB-KW

Keywordsi

Molecular functionGuanine-nucleotide releasing factor
Biological processAutophagy, Transcription, Transcription regulation

Enzyme and pathway databases

SIGNORiQ8TEV9

Names & Taxonomyi

Protein namesi
Recommended name:
Guanine nucleotide exchange protein SMCR8Curated
Alternative name(s):
Smith-Magenis syndrome chromosomal region candidate gene 8 proteinImported
Gene namesi
Name:SMCR8Imported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000176994.10
HGNCiHGNC:17921 SMCR8
neXtProtiNX_Q8TEV9

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi402S → A: Impaired autophagosome maturation; when associated with A-796. 1 Publication1
Mutagenesisi402S → D: Phosphomimetic mutant; able to promote autophagosome maturation; when associated with D-796. 1 Publication1
Mutagenesisi796T → A: Impaired autophagosome maturation; when associated with A-402. 1 Publication1
Mutagenesisi796T → D: Phosphomimetic mutant; able to promote autophagosome maturation; when associated with D-402. 1 Publication1

Organism-specific databases

OpenTargetsiENSG00000176994
PharmGKBiPA38266

Polymorphism and mutation databases

BioMutaiSMCR8
DMDMi147733168

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002874691 – 937Guanine nucleotide exchange protein SMCR8Add BLAST937

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei402Phosphoserine; by TBK11 Publication1
Modified residuei417PhosphoserineCombined sources1
Modified residuei468PhosphoserineCombined sources1
Modified residuei471PhosphoserineCombined sources1
Modified residuei489PhosphoserineCombined sources1
Modified residuei492PhosphoserineCombined sources1
Modified residuei498PhosphoserineCombined sources1
Modified residuei790PhosphoserineCombined sources1
Modified residuei796Phosphothreonine; by TBK11 Publication1

Post-translational modificationi

Phosphorylation by TBK1 is required to promote autophagosome maturation (PubMed:27103069). Phosphorylated by ULK1 (PubMed:27103069).1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ8TEV9
MaxQBiQ8TEV9
PaxDbiQ8TEV9
PeptideAtlasiQ8TEV9
PRIDEiQ8TEV9

PTM databases

iPTMnetiQ8TEV9
PhosphoSitePlusiQ8TEV9

Expressioni

Tissue specificityi

Expressed in all tissues tested.1 Publication

Gene expression databases

BgeeiENSG00000176994
CleanExiHS_SMCR8
GenevisibleiQ8TEV9 HS

Organism-specific databases

HPAiHPA021557
HPA024646

Interactioni

Subunit structurei

Interacts with C9orf72; the interaction is direct (PubMed:27559131, PubMed:27617292). Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex associates with the ATG1/ULK1 kinase complex (PubMed:28195531).5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
C9orf72Q96LT74EBI-2961718,EBI-2961725

GO - Molecular functioni

  • guanyl-nucleotide exchange factor activity Source: UniProtKB-KW
  • protein kinase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi126704, 11 interactors
IntActiQ8TEV9, 12 interactors
STRINGi9606.ENSP00000385025

Structurei

3D structure databases

ProteinModelPortaliQ8TEV9
SMRiQ8TEV9
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini48 – 220uDENN FLCN/SMCR8-typePROSITE-ProRule annotation1 PublicationAdd BLAST173
Domaini318 – 835cDENN FLCN/SMCR8-typePROSITE-ProRule annotation1 PublicationAdd BLAST518
Domaini844 – 910dDENN FLCN/SMCR8-typePROSITE-ProRule annotation1 PublicationAdd BLAST67

Sequence similaritiesi

Belongs to the SMCR8 family.Curated

Phylogenomic databases

eggNOGiENOG410IE98 Eukaryota
ENOG410XQXP LUCA
GeneTreeiENSGT00390000010052
HOGENOMiHOG000154344
HOVERGENiHBG058947
InParanoidiQ8TEV9
OMAiQKWKLIG
OrthoDBiEOG091G0N81
PhylomeDBiQ8TEV9
TreeFamiTF330880

Family and domain databases

InterProiView protein in InterPro
IPR037521 FLCN/SMCR8_DENN
IPR037520 Folliculin_N
PfamiView protein in Pfam
PF11704 Folliculin, 1 hit
PROSITEiView protein in PROSITE
PS51834 DENN_FLCN_SMCR8, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8TEV9-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MISAPDVVAF TKEEEYEEEP YNEPALPEEY SVPLFPFASQ GANPWSKLSG
60 70 80 90 100
AKFSRDFILI SEFSEQVGPQ PLLTIPNDTK VFGTFDLNYF SLRIMSVDYQ
110 120 130 140 150
ASFVGHPPGS AYPKLNFVED SKVVLGDSKE GAFAYVHHLT LYDLEARGFV
160 170 180 190 200
RPFCMAYISA DQHKIMQQFQ ELSAEFSRAS ECLKTGNRKA FAGELEKKLK
210 220 230 240 250
DLDYTRTVLH TETEIQKKAN DKGFYSSQAI EKANELASVE KSIIEHQDLL
260 270 280 290 300
KQIRSYPHRK LKGHDLCPGE MEHIQDQASQ ASTTSNPDES ADTDLYTCRP
310 320 330 340 350
AYTPKLIKAK STKCFDKKLK TLEELCDTEY FTQTLAQLSH IEHMFRGDLC
360 370 380 390 400
YLLTSQIDRA LLKQQHITNF LFEDFVEVDD RMVEKQESIP SKPSQDRPPS
410 420 430 440 450
SSLEECPIPK VLISVGSYKS SVESVLIKME QELGDEEYKE VEVTELSSFD
460 470 480 490 500
PQENLDYLDM DMKGSISSGE SIEVLGTEKS TSVLSKSDSQ ASLTVPLSPQ
510 520 530 540 550
VVRSKAVSHR TISEDSIEVL STCPSEALIP DDFKASYPSA INEEESYPDG
560 570 580 590 600
NEGAIRFQAS ISPPELGETE EGSIENTPSQ IDSSCCIGKE SDGQLVLPST
610 620 630 640 650
PAHTHSDEDG VVSSPPQRHR QKDQGFRVDF SVENANPSSR DNSCEGFPAY
660 670 680 690 700
ELDPSHLLAS RDISKTSLDN YSDTTSYVSS VASTSSDRIP SAYPAGLSSD
710 720 730 740 750
RHKKRAGQNA LKFIRQYPFA HPAIYSLLSG RTLVVLGEDE AIVRKLVTAL
760 770 780 790 800
AIFVPSYGCY AKPVKHWASS PLHIMDFQKW KLIGLQRVAS PAGAGTLHAL
810 820 830 840 850
SRYSRYTSIL DLDNKTLRCP LYRGTLVPRL ADHRTQIKRG STYYLHVQSM
860 870 880 890 900
LTQLCSKAFL YTFCHHLHLP THDKETEELV ASRQMSFLKL TLGLVNEDVR
910 920 930
VVQYLAELLK LHYMQESPGT SHPMLRFDYV PSFLYKI
Length:937
Mass (Da):105,022
Last modified:May 15, 2007 - v2
Checksum:i53A4EF9B3107248F
GO
Isoform 2 (identifier: Q8TEV9-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     788-937: Missing.

Show »
Length:787
Mass (Da):87,755
Checksum:i7F872839B3DAA5A2
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_032309524P → L1 PublicationCorresponds to variant dbSNP:rs8080966Ensembl.1
Natural variantiVAR_032310556R → H1 PublicationCorresponds to variant dbSNP:rs1563632Ensembl.1
Natural variantiVAR_032311636N → S. Corresponds to variant dbSNP:rs12449313Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_025487788 – 937Missing in isoform 2. 1 PublicationAdd BLAST150

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF467440 mRNA Translation: AAL78337.1
BC001018 mRNA Translation: AAH01018.1 Different termination.
BC101116 mRNA Translation: AAI01117.1
BC101117 mRNA Translation: AAI01118.1
BC014179 mRNA Translation: AAH14179.1 Different termination.
BC142680 mRNA Translation: AAI42681.1
CCDSiCCDS11195.2 [Q8TEV9-1]
RefSeqiNP_658988.2, NM_144775.2 [Q8TEV9-1]
UniGeneiHs.592944
Hs.707728

Genome annotation databases

EnsembliENST00000406438; ENSP00000385025; ENSG00000176994 [Q8TEV9-1]
ENST00000639332; ENSP00000492062; ENSG00000283741 [Q8TEV9-1]
GeneIDi140775
KEGGihsa:140775
UCSCiuc002gsy.5 human [Q8TEV9-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiSMCR8_HUMAN
AccessioniPrimary (citable) accession number: Q8TEV9
Secondary accession number(s): A5PKZ5, Q3ZCN0, Q6PJL3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 15, 2007
Last sequence update: May 15, 2007
Last modified: May 23, 2018
This is version 107 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. SIMILARITY comments
    Index of protein domains and families

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