AMBRA1
entrez
55626
canonical
uniprot
Q9C0C7
canonical
ensembl
ENSG00000110497
resolver
ensp
ENSP00000318313
resolver
ensp
ENSP00000415327
resolver
ensp
ENSP00000431926
resolver
ensp
ENSP00000433372
resolver
ensp
ENSP00000508322
resolver
enst
ENST00000533727
resolver
genesymbol
AMBRA1
resolver
genesymbol_syn
DCAF3
resolver
genesymbol_syn
KIAA1736
resolver
hgnc
HGNC:25990
resolver
uniprot
A0A075B6T1
resolver
uniprot
A6XN33
resolver
uniprot
D3DQP8
resolver
uniprot
G3V193
resolver
uniprot
Q86XD6
resolver
uniprot
Q9H8Z0
resolver
uniprot
Q9NXE7
resolver
uniprot_entry
A0A075B6T1_HUMAN
resolver
uniprot_entry
AMRA1_HUMAN
resolver
uniprot_sec
A6XN33
resolver
uniprot_sec
D3DQP8
resolver
uniprot_sec
G3V193
resolver
uniprot_sec
Q86XD6
resolver
uniprot_sec
Q9H8Z0
resolver
uniprot_sec
Q9NXE7
resolver
amino_acid_sequence
MKVVPEKNAVRILWGRERGARAMGAQRLLQELVEDKTRWMKWEGKRVELPDSPRSTFLLAFSPDRTLLASTHVNHNIYITEVKTGKCVHSLIGHRRTPWCVTFHPTISGLIASGCLDGEVRIWDLHGGSESWFTDSNNAIASLAFHPTAQLLLIATANEIHFWDWSRREPFAVVKTASEMERVRLVRFDPLGHYLLTAIVNPSNQQGDDEPEIPIDGTELSHYRQRALLQSQPVRRTPLLHNFLHMLSSRSSGIQVGEQSTVQDSATPSPPPPPPQPSTERPRTSAYIRLRQRVSYPTAECCQHLGILCLCSRCSGTRVPSLLPHQDSVPPASARATTPSFSFVQTEPFHPPEQASSTQQDQGLLNRPSAFSTVQSSTAGNTLRNLSLGPTRRSLGGPLSSHPSRYHREIAPGLTGSEWTRTVLSLNSRSEAESMPPPRTSASSVSLLSVLRQQEGGSQASVYTSATEGRGFPASGLATESDGGNGSSQNNSGSIRHELQCDLRRFFLEYDRLQELDQSLSGEAPQTQQAQEMLNNNIESERPGPSHQPTPHSSENNSNLSRGHLNRCRACHNLLTFNNDTLRWERTTPNYSSGEASSSWQVPSSFESVPSSGSQLPPLERTEGQTPSSSRLELSSSASPQEERTVGVAFNQETGHWERIYTQSSRSGTVSQEALHQDMPEESSEEDSLRRRLLESSLISLSRYDGAGSREHPIYPDPARLSPAAYYAQRMIQYLSRRDSIRQRSMRYQQNRLRSSTSSSSSDNQGPSVEGTDLEFEDFEDNGDRSRHRAPRNARMSAPSLGRFVPRRFLLPEYLPYAGIFHERGQPGLATHSSVNRVLAGAVIGDGQSAVASNIANTTYRLQWWDFTKFDLPEISNASVNVLVQNCKIYNDASCDISADGQLLAAFIPSSQRGFPDEGILAVYSLAPHNLGEMLYTKRFGPNAISVSLSPMGRYVMVGLASRRILLHPSTEHMVAQVFRLQQAHGGETSMRRVFNVLYPMPADQRRHVSINSARWLPEPGLGLAYGTNKGDLVICRPEALNSGVEYYWDQLNETVFTVHSNSRSSERPGTSRATWRTDRDMGLMNAIGLQPRNPATSVTSQGTQTLALQLQNAETQTEREVPEPGTAASGPGEGEGSEYGASGEDALSRIQRLMAEGGMTAVVQREQSTTMASMGGFGNNIIVSHRIHRSSQTGTEPGAAHTSSPQPSTSRGLLPEAGQLAERGLSPRTASWDQPGTPGREPTQPTLPSSSPVPIPVSLPSAEGPTLHCELTNNNHLLDGGSSRGDAAGPRGEPRNR
uniprot
proteins
function
FUNCTION: Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex involved in cell cycle control and autophagy (PubMed:20921139, PubMed:23524951, PubMed:24587252, PubMed:32333458, PubMed:33854232, PubMed:33854235, PubMed:33854239). The DCX(AMBRA1) complex specifically mediates the polyubiquitination of target proteins such as BECN1, CCND1, CCND2, CCND3, ELOC and ULK1 (PubMed:23524951, PubMed:33854232, PubMed:33854235, PubMed:33854239). Acts as an upstream master regulator of the transition from G1 to S cell phase: AMBRA1 specifically recognizes and binds phosphorylated cyclin-D (CCND1, CCND2 and CCND3), leading to cyclin-D ubiquitination by the DCX(AMBRA1) complex and subsequent degradation (PubMed:33854232, PubMed:33854235, PubMed:33854239). By controlling the transition from G1 to S phase and cyclin-D degradation, AMBRA1 acts as a tumor suppressor that promotes genomic integrity during DNA replication and counteracts developmental abnormalities and tumor growth (PubMed:33854232, PubMed:33854235, PubMed:33854239). AMBRA1 also regulates the cell cycle by promoting MYC dephosphorylation and degradation independently of the DCX(AMBRA1) complex: acts via interaction with the catalytic subunit of protein phosphatase 2A (PPP2CA), which enhances interaction between PPP2CA and MYC, leading to MYC dephosphorylation and degradation (PubMed:25438055, PubMed:25803737). Acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes (PubMed:25499913, PubMed:30166453). Acts as a key regulator of autophagy by modulating the BECN1-PIK3C3 complex: controls protein turnover during neuronal development, and regulates normal cell survival and proliferation (PubMed:21358617). In normal conditions, AMBRA1 is tethered to the cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2 (PubMed:20921139). Upon autophagy induction, AMBRA1 is released from the cytoskeletal docking site to induce autophagosome nucleation by mediating ubiquitination of proteins involved in autophagy (PubMed:20921139). The DCX(AMBRA1) complex mediates 'Lys-63'-linked ubiquitination of BECN1, increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity (By similarity). In collaboration with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1 following autophagy induction, promoting ULK1 stability and kinase activity (PubMed:23524951). Also activates ULK1 via interaction with TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains (PubMed:31123703). Also acts as an activator of mitophagy via interaction with PRKN and LC3 proteins (MAP1LC3A, MAP1LC3B or MAP1LC3C); possibly by bringing damaged mitochondria onto autophagosomes (PubMed:21753002, PubMed:25215947). Also activates mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-mediated ubiquitination of MFN2 (PubMed:30217973). AMBRA1 is also involved in regulatory T-cells (Treg) differentiation by promoting FOXO3 dephosphorylation independently of the DCX(AMBRA1) complex: acts via interaction with PPP2CA, which enhances interaction between PPP2CA and FOXO3, leading to FOXO3 dephosphorylation and stabilization (PubMed:30513302). May act as a regulator of intracellular trafficking, regulating the localization of active PTK2/FAK and SRC (By similarity). Also involved in transcription regulation by acting as a scaffold for protein complexes at chromatin (By similarity). {ECO:0000250|UniProtKB:A2AH22, ECO:0000269|PubMed:20921139, ECO:0000269|PubMed:21358617, ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:24587252, ECO:0000269|PubMed:25215947, ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:25499913, ECO:0000269|PubMed:25803737, ECO:0000269|PubMed:30166453, ECO:0000269|PubMed:30217973, ECO:0000269|PubMed:30513302, ECO:0000269|PubMed:31123703, ECO:0000269|PubMed:32333458, ECO:0000269|PubMed:33854232, ECO:0000269|PubMed:33854235, ECO:0000269|PubMed:33854239}.
uniprot
proteins
mass_dalton
142507
uniprot
proteins
mutagenesis
MUTAGEN 1..43; /note="Missing: Abolished interaction with DDB1."; /evidence="ECO:0000269|PubMed:30166453"; MUTAGEN 1..22; /note="Missing: Abolished interaction with DDB1."; /evidence="ECO:0000269|PubMed:30166453"; MUTAGEN 52; /note="S->A: Impaired phosphorylation by MTOR, leading to strong induction of autophagy. Does not affect interaction with DDB1."; /evidence="ECO:0000269|PubMed:23524951"; MUTAGEN 52; /note="S->E: Phospho-mimetic mutant; abolished ability to promote autophagy. Does not affect interaction with DDB1."; /evidence="ECO:0000269|PubMed:23524951"; MUTAGEN 275..277; /note="PQP->AQA: Abolished interaction with PPP2CA and MYC, leading to decreased MYC dephosphorylation; when associated with 1206-A--A-1208. Abolished interaction with PPP2CA and FOXO3, leading to decreased FOXO3 dephosphorylation; when associated with 1206-A--A-1208."; /evidence="ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:30513302"; MUTAGEN 482; /note="D->A: Abolished cleavage by caspases without affecting cleavage by calpains."; /evidence="ECO:0000269|PubMed:22441670"; MUTAGEN 620; /note="E->A: Abolished interaction with TRAF6."; /evidence="ECO:0000269|PubMed:23524951"; MUTAGEN 642; /note="E->A: Does not affect interaction with TRAF6."; /evidence="ECO:0000269|PubMed:23524951"; MUTAGEN 682; /note="E->A: Abolished interaction with TRAF6."; /evidence="ECO:0000269|PubMed:23524951"; MUTAGEN 918; /note="E->A: Does not affect interaction with TRAF6."; /evidence="ECO:0000269|PubMed:23524951"; MUTAGEN 1043; /note="S->A: Abolished phosphorylation by CHUK/IKKA, leading to impaired interaction with ATG8 family proteins and reduced mitophagic activity."; /evidence="ECO:0000269|PubMed:30217973"; MUTAGEN 1043; /note="S->D: Phospho-mimetic mutant; increased interaction with ATG8 family proteins and increased mitophagic activity."; /evidence="ECO:0000269|PubMed:30217973"; MUTAGEN 1049..1052; /note="WDQL->ADQA: Abolished interaction with LC3 (MAP1LC3A, MAP1LC3B or MAP1LC3C)."; /evidence="ECO:0000269|PubMed:25215947"; MUTAGEN 1105; /note="Q->A: In TAT1 mutant; abolished interaction with DYNLL1 and DYNLL2, leading to constitutive induction of autophagy."; /evidence="ECO:0000269|PubMed:20921139"; MUTAGEN 1117; /note="Q->A: In TAT2 mutant; abolished interaction with DYNLL1 and DYNLL2, leading to constitutive induction of autophagy."; /evidence="ECO:0000269|PubMed:20921139"; MUTAGEN 1134; /note="E->A: Does not affect interaction with TRAF6."; /evidence="ECO:0000269|PubMed:23524951"; MUTAGEN 1206..1208; /note="PQP->AQA: Abolished interaction with PPP2CA and MYC, leading to decreased MYC dephosphorylation; when associated with 275-A--A-277. Abolished interaction with PPP2CA and FOXO3, leading to decreased FOXO3 dephosphorylation; when associated with 275-A--A-277."; /evidence="ECO:0000269|PubMed:25438055
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:30166453, ECO:0000269|PubMed:33854232, ECO:0000269|PubMed:33854235, ECO:0000269|PubMed:33854239}.
uniprot
proteins
post_translational_modification
PTM: Phosphorylation at Ser-52 by MTOR inhibits its ability to regulate autophagy and mediate ubiquitination of ULK1 (PubMed:23524951). Phosphorylation by ULK1 in response to autophagy induction abolishes interaction with DYNLL1 and DYNLL2, releasing AMBRA1 from the cytoskeletal docking site to induce autophagosome nucleation (PubMed:20921139). Phosphorylation by MTOR inhibits interaction with PPP2CA and subsequent dephosphorylation of MYC (PubMed:25438055). Phosphorylation at Ser-1043 by CHUK/IKKA promotes its interaction with ATG8 family proteins GABARAP and MAP1LC3B and its mitophagic activity (PubMed:30217973). {ECO:0000269|PubMed:20921139, ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:30217973}.; PTM: Ubiquitinated by RNF2 via 'Lys-48'-linkage in unstressed cells, leading to its degradation by the proteasome (PubMed:25499913). Induction of autophagy promotes stabilization via interaction with CUL4 (CUL4A or CUL4B) and DDB1 (PubMed:25499913). Upon prolonged starvation, ubiquitinated and degraded, terminating the autophagy response (PubMed:25499913). {ECO:0000269|PubMed:25499913}.; PTM: Undergoes proteolytic processing by caspase-6 (CASP6), caspase-7 (CASP7) and caspase-8 (CASP8) during apoptosis, resulting in the dismantling of the autophagic machinery and the accomplishment of the programmed cell death program (PubMed:22441670). Also cleaved by calpains during apoptosis, which mediate a complete proteolytic degradation (PubMed:22441670). {ECO:0000269|PubMed:22441670}.
uniprot
proteins
protein_family
WD repeat AMBRA1 family
uniprot
proteins
pubmed
11214970
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16554811
uniprot
proteins
pubmed
16949367
uniprot
proteins
pubmed
17589504
uniprot
proteins
pubmed
17974005
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20921139
uniprot
proteins
pubmed
21358617
uniprot
proteins
pubmed
21753002
uniprot
proteins
pubmed
22441670
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23524951
uniprot
proteins
pubmed
23954414
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24587252
uniprot
proteins
pubmed
25215947
uniprot
proteins
pubmed
25438055
uniprot
proteins
pubmed
25499913
uniprot
proteins
pubmed
25803737
uniprot
proteins
pubmed
25925585
uniprot
proteins
pubmed
28059583
uniprot
proteins
pubmed
30166453
uniprot
proteins
pubmed
30217973
uniprot
proteins
pubmed
30513302
uniprot
proteins
pubmed
31123703
uniprot
proteins
pubmed
32333458
uniprot
proteins
pubmed
32616651
uniprot
proteins
pubmed
33854232
uniprot
proteins
pubmed
33854235
uniprot
proteins
pubmed
33854239
uniprot
proteins
sequence_length
1298
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000269|PubMed:20921139}. Cytoplasm, cytoskeleton {ECO:0000269|PubMed:20921139}. Cytoplasmic vesicle, autophagosome {ECO:0000250|UniProtKB:A2AH22}. Mitochondrion {ECO:0000269|PubMed:21358617, ECO:0000269|PubMed:25215947}. Cytoplasm, cytosol {ECO:0000250|UniProtKB:A2AH22}. Nucleus {ECO:0000269|PubMed:32616651}. Cell junction, focal adhesion {ECO:0000250|UniProtKB:A2AH22}. Note=Localizes to the cytoskeleton in absence of autophagy induction (PubMed:20921139). Upon autophagy induction, AMBRA1 relocalizes to the endoplasmic reticulum to enable autophagosome nucleation (PubMed:20921139). Partially localizes at mitochondria in normal conditions (PubMed:21358617). Also localizes to discrete punctae along the ciliary axoneme (By similarity). {ECO:0000250|UniProtKB:A2AH22, ECO:0000269|PubMed:20921139, ECO:0000269|PubMed:21358617}.
uniprot
proteins