Ambra1
entrez
228361
canonical
uniprot
A2AH22
canonical
ensembl
ENSMUSG00000040506
resolver
ensp
ENSMUSP00000049258
resolver
ensp
ENSMUSP00000097299
resolver
ensp
ENSMUSP00000106949
resolver
ensp
ENSMUSP00000166091
resolver
genesymbol
Ambra1
resolver
genesymbol_syn
Kiaa1736
resolver
uniprot
A2AH21
resolver
uniprot
A2AH24
resolver
uniprot
Q3TF60
resolver
uniprot
Q3U239
resolver
uniprot
Q3UF70
resolver
uniprot
Q6ZPJ1
resolver
uniprot
Q8BJJ8
resolver
uniprot
Q8BYW8
resolver
uniprot_entry
AMRA1_MOUSE
resolver
uniprot_sec
A2AH21
resolver
uniprot_sec
A2AH24
resolver
uniprot_sec
Q3TF60
resolver
uniprot_sec
Q3U239
resolver
uniprot_sec
Q3UF70
resolver
uniprot_sec
Q6ZPJ1
resolver
uniprot_sec
Q8BJJ8
resolver
uniprot_sec
Q8BYW8
resolver
amino_acid_sequence
MKVVPEKNAVRILWGRERGTRAMGAQRLLQELVEDKTRWMKWEGKRVELPDSPRSTFLLAFSPDRTLLASTHVNHNIYITEVKTGKCVHSLIGHRRTPWCVTFHPTISGLIASGCLDGEVRIWDLHGGSESWFTDSNNAIASLAFHPTAQLLLIATANEIHFWDWSRREPFAVVKTASEMERVRLVRFDPLGHYLLTAIVNPSNQQGDDEPEIPIDGTELSHYRQRALLQSQPVRRTPLLHNFLHMLSSRSSGIQVGEQSTVQDSATPSPPPPPPQPSTERPRTSAYIRLRQRVSYPTTVECCQHPGILCLCSRCAGTRVPSLLPHQDSVPPASARATTPSFSFVQTEPFHPPEQASSTQQDQGLLNRPSAFSTVQSSTAGNTLRNLSLGPTRRSLGGPLSSHPSRYHRELAPGLTGSEWTRTVLTLNSRSEVESMPPPRTSASSVSLLSVLRQQEGGSQASVYTSATEGRGFPSSGLATESDGGNGSSQNNSGSIRHELQCDLRRFFLEYDRLQELDQSLSGETPQTQQAQEMLNNNIESERPGPSHLPTPHSSENNSNLSRGHLNRCRACHNLLTFNNDTLRWERTTPNYSSGEASSSWHVSTTFEGMPPSGNQLPPLERTEGQMPSSSRLELSSSASSQEERTVGVAFNQETGHWERIYTQSSRSGTVSQEALHQDMPEESSEEDSLRRRLLESSLISLSRYDGAGSREHPIYPDPARLSPAAYYAQRMIQYLSRRDSIRQRSMRYQQNRLRSSTSSSSSDNQGPSVEGTDLEFEDFEDNGDRSRHRAPRNARMSAPSLGRFVPRRFLLPEYLPYAGIFHERGQPGLATHSSVNRVLAGAVIGDGQSAVASNIANTTYRLQWWDFTKFDLPEISNASVNVLVQNCKIYNDASCDISADGQLLAAFIPSSQRGFPDEGILAVYSLAPHNLGEMLYTKRFGPNAISVSLSPMGRYVMVGLASRRILLHPSTEHMVAQVFRLQQAHGGETSMRRVFNVLYPMPADQRRHVSINSARWLPEPGLGLAYGTNKGDLVICRPEALNSGIEYYWDQLSETVFTVHSSSRSSERPGTSRATWRTDRDMGLMNAIGLQPRNPTTSVTSQGTQTLALQLQNAETQTEREEEEPGAASSGPGEGEGSEYGGSGEDALSRIQRLMAEGGMTAVVQREQSTTMASMGGFGNNIIVSHRIHRSSQTGTESGAARTSSPQPSTSRGLPSEPGQLAERALSPRTASWDQPSTSGRELPQPALSSSSPVPIPVPLASNEGPTMHCNVTNNSHLPEGDGSNRGEAAGPSGEPQNR
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:17589504, 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:23974797, 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). 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 (By similarity). 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:17589504). In normal conditions, AMBRA1 is tethered to the cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2 (By similarity). Upon autophagy induction, AMBRA1 is released from the cytoskeletal docking site to induce autophagosome nucleation by mediating ubiquitination of proteins involved in autophagy (By similarity). The DCX(AMBRA1) complex mediates 'Lys-63'-linked ubiquitination of BECN1, increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity (PubMed:23974797). In collaboration with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1 following autophagy induction, promoting ULK1 stability and kinase activity (By similarity). Also activates ULK1 via interaction with TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains (By similarity). 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 (By similarity). 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:28789945, PubMed:30513302). May act as a regulator of intracellular trafficking, regulating the localization of active PTK2/FAK and SRC (PubMed:28362576). Also involved in transcription regulation by acting as a scaffold for protein complexes at chromatin (PubMed:32616651). {ECO:0000250|UniProtKB:Q9C0C7, ECO:0000269|PubMed:17589504, ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:23974797, ECO:0000269|PubMed:25215947, ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:28362576, ECO:0000269|PubMed:28789945, ECO:0000269|PubMed:30513302, ECO:0000269|PubMed:32616651, ECO:0000269|PubMed:33854232, ECO:0000269|PubMed:33854235, ECO:0000269|PubMed:33854239}.
uniprot
proteins
mass_dalton
142879
uniprot
proteins
mutagenesis
MUTAGEN 2; /note="K->R: Does not affect ubiquitination by RNF2."; /evidence="ECO:0000269|PubMed:24980959"; MUTAGEN 7; /note="K->R: Does not affect ubiquitination by RNF2."; /evidence="ECO:0000269|PubMed:24980959"; MUTAGEN 36; /note="K->R: Does not affect ubiquitination by RNF2."; /evidence="ECO:0000269|PubMed:24980959"; MUTAGEN 41; /note="K->R: Does not affect ubiquitination by RNF2."; /evidence="ECO:0000269|PubMed:24980959"; MUTAGEN 45; /note="K->R: Abolished ubiquitination by RNF2."; /evidence="ECO:0000269|PubMed:24980959
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:23974797, 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. 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. Phosphorylation by MTOR inhibits interaction with PPP2CA and subsequent dephosphorylation of MYC. Phosphorylation at Ser-1044 by CHUK/IKKA promotes its interaction with ATG8 family proteins GABARAP and MAP1LC3B and its mitophagic activity. {ECO:0000250|UniProtKB:Q9C0C7}.; PTM: Ubiquitinated by RNF2 via 'Lys-48'-linkage in unstressed cells, leading to its degradation by the proteasome (PubMed:24980959). Induction of autophagy promotes stabilization via interaction with CUL4 (CUL4A or CUL4B) and DDB1. Upon prolonged starvation, ubiquitinated and degraded, terminating the autophagy response (By similarity). {ECO:0000250|UniProtKB:Q9C0C7, ECO:0000269|PubMed:24980959}.; 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. Also cleaved by calpains during apoptosis, which mediate a complete proteolytic degradation. {ECO:0000250|UniProtKB:Q9C0C7}.
uniprot
proteins
protein_family
WD repeat AMBRA1 family
uniprot
proteins
pubmed
14621295
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
17589504
uniprot
proteins
pubmed
17603510
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
21753002
uniprot
proteins
pubmed
23974797
uniprot
proteins
pubmed
24089209
uniprot
proteins
pubmed
24129315
uniprot
proteins
pubmed
24980959
uniprot
proteins
pubmed
25215947
uniprot
proteins
pubmed
25438055
uniprot
proteins
pubmed
25925585
uniprot
proteins
pubmed
28362576
uniprot
proteins
pubmed
28789945
uniprot
proteins
pubmed
30513302
uniprot
proteins
pubmed
32616651
uniprot
proteins
pubmed
33854232
uniprot
proteins
pubmed
33854235
uniprot
proteins
pubmed
33854239
uniprot
proteins
sequence_length
1300
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9C0C7}. Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:Q9C0C7}. Cytoplasmic vesicle, autophagosome {ECO:0000305|PubMed:17589504, ECO:0000305|PubMed:24089209, ECO:0000305|PubMed:28362576, ECO:0000305|PubMed:32616651}. Mitochondrion {ECO:0000250|UniProtKB:Q9C0C7}. Cytoplasm, cytosol {ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:24980959}. Nucleus {ECO:0000269|PubMed:24980959, ECO:0000269|PubMed:28362576, ECO:0000269|PubMed:32616651}. Cell junction, focal adhesion {ECO:0000269|PubMed:28362576}. Note=Localizes to the cytoskeleton in absence of autophagy induction. Upon autophagy induction, AMBRA1 relocalizes to the endoplasmic reticulum to enable autophagosome nucleation (By similarity). Partially localizes at mitochondria in normal conditions (By similarity). Also localizes to discrete punctae along the ciliary axoneme (PubMed:24089209). {ECO:0000250|UniProtKB:Q9C0C7, ECO:0000269|PubMed:24089209}.
uniprot
proteins