AMRA1_MOUSE
ID AMRA1_MOUSE Reviewed; 1300 AA.
AC A2AH22; A2AH21; A2AH24; Q3TF60; Q3U239; Q3UF70; Q6ZPJ1; Q8BJJ8; Q8BYW8;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 1.
DT 03-AUG-2022, entry version 127.
DE RecName: Full=Activating molecule in BECN1-regulated autophagy protein 1 {ECO:0000303|PubMed:17589504};
GN Name=Ambra1 {ECO:0000303|PubMed:17589504, ECO:0000312|MGI:MGI:2443564};
GN Synonyms=Kiaa1736 {ECO:0000303|PubMed:14621295};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 3; 4 AND 5).
RC STRAIN=C57BL/6J, and NOD; TISSUE=Sympathetic ganglion, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND ALTERNATIVE SPLICING.
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 126-1300.
RC TISSUE=Embryonic tail;
RX PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:167-180(2003).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, DEVELOPMENTAL STAGE,
RP AND INTERACTION WITH BECN1 AND PIK3C3.
RX PubMed=17589504; DOI=10.1038/nature05925;
RA Maria Fimia G., Stoykova A., Romagnoli A., Giunta L., Di Bartolomeo S.,
RA Nardacci R., Corazzari M., Fuoco C., Ucar A., Schwartz P., Gruss P.,
RA Piacentini M., Chowdhury K., Cecconi F.;
RT "Ambra1 regulates autophagy and development of the nervous system.";
RL Nature 447:1121-1125(2007).
RN [5]
RP REVIEW.
RX PubMed=17603510; DOI=10.1038/ncb0707-741;
RA Le Bot N.;
RT "Autophagy: a new regulator of development.";
RL Nat. Cell Biol. 9:741-741(2007).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH
RP PRKN.
RX PubMed=21753002; DOI=10.1523/jneurosci.1917-11.2011;
RA Van Humbeeck C., Cornelissen T., Hofkens H., Mandemakers W., Gevaert K.,
RA De Strooper B., Vandenberghe W.;
RT "Parkin interacts with Ambra1 to induce mitophagy.";
RL J. Neurosci. 31:10249-10261(2011).
RN [7]
RP SUBCELLULAR LOCATION.
RX PubMed=24089209; DOI=10.1038/nature12639;
RA Pampliega O., Orhon I., Patel B., Sridhar S., Diaz-Carretero A., Beau I.,
RA Codogno P., Satir B.H., Satir P., Cuervo A.M.;
RT "Functional interaction between autophagy and ciliogenesis.";
RL Nature 502:194-200(2013).
RN [8]
RP FUNCTION, IDENTIFICATION IN A DCX (DDB1-CUL4-X-BOX) E3 UBIQUITIN-PROTEIN
RP LIGASE COMPLEX, PATHWAY, AND INTERACTION WITH BECN1.
RX PubMed=23974797; DOI=10.1038/emboj.2013.189;
RA Xia P., Wang S., Du Y., Zhao Z., Shi L., Sun L., Huang G., Ye B., Li C.,
RA Dai Z., Hou N., Cheng X., Sun Q., Li L., Yang X., Fan Z.;
RT "WASH inhibits autophagy through suppression of Beclin 1 ubiquitination.";
RL EMBO J. 32:2685-2696(2013).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION AT LYS-45, AND MUTAGENESIS
RP OF LYS-2; LYS-7; LYS-36; LYS-41 AND LYS-45.
RX PubMed=24980959; DOI=10.1038/cr.2014.85;
RA Xia P., Wang S., Huang G., Du Y., Zhu P., Li M., Fan Z.;
RT "RNF2 is recruited by WASH to ubiquitinate AMBRA1 leading to downregulation
RT of autophagy.";
RL Cell Res. 24:943-958(2014).
RN [10]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-748, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryo;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
RN [11]
RP FUNCTION.
RX PubMed=25215947; DOI=10.1038/cdd.2014.139;
RA Strappazzon F., Nazio F., Corrado M., Cianfanelli V., Romagnoli A.,
RA Fimia G.M., Campello S., Nardacci R., Piacentini M., Campanella M.,
RA Cecconi F.;
RT "AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN
RT and p62/SQSTM1.";
RL Cell Death Differ. 22:419-432(2015).
RN [12]
RP FUNCTION, AND INTERACTION WITH PPP2CA.
RX PubMed=25438055; DOI=10.1038/ncb3072;
RA Cianfanelli V., Fuoco C., Lorente M., Salazar M., Quondamatteo F.,
RA Gherardini P.F., De Zio D., Nazio F., Antonioli M., D'Orazio M., Skobo T.,
RA Bordi M., Rohde M., Dalla Valle L., Helmer-Citterich M., Gretzmeier C.,
RA Dengjel J., Fimia G.M., Piacentini M., Di Bartolomeo S., Velasco G.,
RA Cecconi F.;
RT "AMBRA1 links autophagy to cell proliferation and tumorigenesis by
RT promoting c-Myc dephosphorylation and degradation.";
RL Nat. Cell Biol. 17:20-30(2015).
RN [13]
RP FUNCTION.
RX PubMed=28789945; DOI=10.1016/j.bbrc.2017.08.019;
RA Akatsuka H., Kuga S., Masuhara K., Davaadorj O., Okada C., Iida Y.,
RA Okada Y., Fukunishi N., Suzuki T., Hosomichi K., Ohtsuka M., Tanaka M.,
RA Inoue I., Kimura M., Sato T.;
RT "AMBRA1 is involved in T cell receptor-mediated metabolic reprogramming
RT through an ATG7-independent pathway.";
RL Biochem. Biophys. Res. Commun. 491:1098-1104(2017).
RN [14]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PTK2 AND SRC.
RX PubMed=28362576; DOI=10.7554/elife.23172;
RA Schoenherr C., Byron A., Sandilands E., Paliashvili K., Baillie G.S.,
RA Garcia-Munoz A., Valacca C., Cecconi F., Serrels B., Frame M.C.;
RT "Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell
RT invasion via trafficking networks.";
RL Elife 6:0-0(2017).
RN [15]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30513302; DOI=10.1016/j.devcel.2018.11.010;
RA Becher J., Simula L., Volpe E., Procaccini C., La Rocca C., D'Acunzo P.,
RA Cianfanelli V., Strappazzon F., Caruana I., Nazio F., Weber G.,
RA Gigantino V., Botti G., Ciccosanti F., Borsellino G., Campello S.,
RA Mandolesi G., De Bardi M., Fimia G.M., D'Amelio M., Ruffini F., Furlan R.,
RA Centonze D., Martino G., Braghetta P., Chrisam M., Bonaldo P., Matarese G.,
RA Locatelli F., Battistini L., Cecconi F.;
RT "AMBRA1 controls regulatory T-cell differentiation and homeostasis upstream
RT of the FOXO3-FOXP3 axis.";
RL Dev. Cell 47:592-607(2018).
RN [16]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=32616651; DOI=10.1074/jbc.ra120.012565;
RA Schoenherr C., Byron A., Griffith B., Loftus A., Wills J.C., Munro A.F.,
RA von Kriegsheim A., Frame M.C.;
RT "The autophagy protein Ambra1 regulates gene expression by supporting novel
RT transcriptional complexes.";
RL J. Biol. Chem. 295:12045-12057(2020).
RN [17]
RP FUNCTION, PATHWAY, AND DISRUPTION PHENOTYPE.
RX PubMed=33854232; DOI=10.1038/s41586-021-03422-5;
RA Maiani E., Milletti G., Nazio F., Holdgaard S.G., Bartkova J., Rizza S.,
RA Cianfanelli V., Lorente M., Simoneschi D., Di Marco M., D'Acunzo P.,
RA Di Leo L., Rasmussen R., Montagna C., Raciti M., De Stefanis C.,
RA Gabicagogeascoa E., Rona G., Salvador N., Pupo E., Merchut-Maya J.M.,
RA Daniel C.J., Carinci M., Cesarini V., O'sullivan A., Jeong Y.T., Bordi M.,
RA Russo F., Campello S., Gallo A., Filomeni G., Lanzetti L., Sears R.C.,
RA Hamerlik P., Bartolazzi A., Hynds R.E., Pearce D.R., Swanton C., Pagano M.,
RA Velasco G., Papaleo E., De Zio D., Maya-Mendoza A., Locatelli F.,
RA Bartek J., Cecconi F.;
RT "AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity.";
RL Nature 592:799-803(2021).
RN [18]
RP FUNCTION, PATHWAY, AND DISRUPTION PHENOTYPE.
RX PubMed=33854235; DOI=10.1038/s41586-021-03445-y;
RA Simoneschi D., Rona G., Zhou N., Jeong Y.T., Jiang S., Milletti G.,
RA Arbini A.A., O'Sullivan A., Wang A.A., Nithikasem S., Keegan S., Siu Y.,
RA Cianfanelli V., Maiani E., Nazio F., Cecconi F., Boccalatte F., Fenyoe D.,
RA Jones D.R., Busino L., Pagano M.;
RT "CRL4AMBRA1 is a master regulator of D-type cyclins.";
RL Nature 592:789-793(2021).
RN [19]
RP FUNCTION, AND PATHWAY.
RX PubMed=33854239; DOI=10.1038/s41586-021-03474-7;
RA Chaikovsky A.C., Li C., Jeng E.E., Loebell S., Lee M.C., Murray C.W.,
RA Cheng R., Demeter J., Swaney D.L., Chen S.H., Newton B.W., Johnson J.R.,
RA Drainas A.P., Shue Y.T., Seoane J.A., Srinivasan P., He A., Yoshida A.,
RA Hipkins S.Q., McCrea E., Poltorack C.D., Krogan N.J., Diehl J.A., Kong C.,
RA Jackson P.K., Curtis C., Petrov D.A., Bassik M.C., Winslow M.M., Sage J.;
RT "The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D.";
RL Nature 592:794-798(2021).
CC -!- FUNCTION: Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3
CC ubiquitin-protein ligase complex involved in cell cycle control and
CC autophagy (PubMed:17589504, PubMed:33854232, PubMed:33854235,
CC PubMed:33854239). The DCX(AMBRA1) complex specifically mediates the
CC polyubiquitination of target proteins such as BECN1, CCND1, CCND2,
CC CCND3, ELOC and ULK1 (PubMed:23974797, PubMed:33854232,
CC PubMed:33854235, PubMed:33854239). Acts as an upstream master regulator
CC of the transition from G1 to S cell phase: AMBRA1 specifically
CC recognizes and binds phosphorylated cyclin-D (CCND1, CCND2 and CCND3),
CC leading to cyclin-D ubiquitination by the DCX(AMBRA1) complex and
CC subsequent degradation (PubMed:33854232, PubMed:33854235,
CC PubMed:33854239). By controlling the transition from G1 to S phase and
CC cyclin-D degradation, AMBRA1 acts as a tumor suppressor that promotes
CC genomic integrity during DNA replication and counteracts developmental
CC abnormalities and tumor growth (PubMed:33854232, PubMed:33854235,
CC PubMed:33854239). AMBRA1 also regulates the cell cycle by promoting MYC
CC dephosphorylation and degradation independently of the DCX(AMBRA1)
CC complex: acts via interaction with the catalytic subunit of protein
CC phosphatase 2A (PPP2CA), which enhances interaction between PPP2CA and
CC MYC, leading to MYC dephosphorylation and degradation
CC (PubMed:25438055). Acts as a regulator of Cul5-RING (CRL5) E3
CC ubiquitin-protein ligase complexes by mediating ubiquitination and
CC degradation of Elongin-C (ELOC) component of CRL5 complexes (By
CC similarity). Acts as a key regulator of autophagy by modulating the
CC BECN1-PIK3C3 complex: controls protein turnover during neuronal
CC development, and regulates normal cell survival and proliferation
CC (PubMed:17589504). In normal conditions, AMBRA1 is tethered to the
CC cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2 (By
CC similarity). Upon autophagy induction, AMBRA1 is released from the
CC cytoskeletal docking site to induce autophagosome nucleation by
CC mediating ubiquitination of proteins involved in autophagy (By
CC similarity). The DCX(AMBRA1) complex mediates 'Lys-63'-linked
CC ubiquitination of BECN1, increasing the association between BECN1 and
CC PIK3C3 to promote PIK3C3 activity (PubMed:23974797). In collaboration
CC with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1
CC following autophagy induction, promoting ULK1 stability and kinase
CC activity (By similarity). Also activates ULK1 via interaction with
CC TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked
CC polyubiquitin chains (By similarity). Also acts as an activator of
CC mitophagy via interaction with PRKN and LC3 proteins (MAP1LC3A,
CC MAP1LC3B or MAP1LC3C); possibly by bringing damaged mitochondria onto
CC autophagosomes (PubMed:21753002, PubMed:25215947). Also activates
CC mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-
CC mediated ubiquitination of MFN2 (By similarity). AMBRA1 is also
CC involved in regulatory T-cells (Treg) differentiation by promoting
CC FOXO3 dephosphorylation independently of the DCX(AMBRA1) complex: acts
CC via interaction with PPP2CA, which enhances interaction between PPP2CA
CC and FOXO3, leading to FOXO3 dephosphorylation and stabilization
CC (PubMed:28789945, PubMed:30513302). May act as a regulator of
CC intracellular trafficking, regulating the localization of active
CC PTK2/FAK and SRC (PubMed:28362576). Also involved in transcription
CC regulation by acting as a scaffold for protein complexes at chromatin
CC (PubMed:32616651). {ECO:0000250|UniProtKB:Q9C0C7,
CC ECO:0000269|PubMed:17589504, ECO:0000269|PubMed:21753002,
CC ECO:0000269|PubMed:23974797, ECO:0000269|PubMed:25215947,
CC ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:28362576,
CC ECO:0000269|PubMed:28789945, ECO:0000269|PubMed:30513302,
CC ECO:0000269|PubMed:32616651, ECO:0000269|PubMed:33854232,
CC ECO:0000269|PubMed:33854235, ECO:0000269|PubMed:33854239}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:23974797, ECO:0000269|PubMed:33854232,
CC ECO:0000269|PubMed:33854235, ECO:0000269|PubMed:33854239}.
CC -!- SUBUNIT: Component of the DCX(AMBRA1) E3 ubiquitin ligase complex, also
CC named CRL4(AMBRA1), at least composed of CUL4 (CUL4A or CUL4B), DDB1,
CC AMBRA1 and RBX1 (PubMed:23974797). Interacts with BECN1
CC (PubMed:17589504, PubMed:23974797). Probably forms a complex with BECN1
CC and PIK3C3 (PubMed:17589504). Interacts with BECN2 (By similarity).
CC Interacts with BCL2; leading to prevent interaction with BCN1 and
CC autophagy, interaction is disrupted upon autophagy induction (By
CC similarity). Interacts with ULK1 (By similarity). Interacts (via PxP
CC motifs) with PPP2CA; enhancing interaction between PPP2CA and MYC or
CC FOXO3 (PubMed:25438055). Forms a complex with PPP2CA and BECN1 (By
CC similarity). Interacts (TQT motifs) with DYNLL1 and DYNLL2; tethering
CC AMBRA1 and the BECN1-PIK3C3 complex in absence of autophagy (By
CC similarity). Interacts with TRAF6; interaction is required to mediate
CC 'Lys-63'-linked ubiquitination of ULK1 (By similarity). Interacts with
CC TRIM32; promoting activation of ULK1 by TRIM32 via unanchored 'Lys-63'-
CC linked polyubiquitin chains (By similarity). Interacts with PRKN
CC (PubMed:21753002). Interacts (via LIR motif) with LC3 (MAP1LC3A,
CC MAP1LC3B or MAP1LC3C) (By similarity). Interacts with HUWE1 (By
CC similarity). Interacts with PTK2/FAK (PubMed:28362576). Interacts with
CC SRC; required for SRC trafficking to autophagosomes (PubMed:28362576).
CC {ECO:0000250|UniProtKB:Q9C0C7, ECO:0000269|PubMed:17589504,
CC ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:23974797,
CC ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:28362576}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:Q9C0C7}. Cytoplasm, cytoskeleton
CC {ECO:0000250|UniProtKB:Q9C0C7}. Cytoplasmic vesicle, autophagosome
CC {ECO:0000305|PubMed:17589504, ECO:0000305|PubMed:24089209,
CC ECO:0000305|PubMed:28362576, ECO:0000305|PubMed:32616651}.
CC Mitochondrion {ECO:0000250|UniProtKB:Q9C0C7}. Cytoplasm, cytosol
CC {ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:24980959}. Nucleus
CC {ECO:0000269|PubMed:24980959, ECO:0000269|PubMed:28362576,
CC ECO:0000269|PubMed:32616651}. Cell junction, focal adhesion
CC {ECO:0000269|PubMed:28362576}. Note=Localizes to the cytoskeleton in
CC absence of autophagy induction. Upon autophagy induction, AMBRA1
CC relocalizes to the endoplasmic reticulum to enable autophagosome
CC nucleation (By similarity). Partially localizes at mitochondria in
CC normal conditions (By similarity). Localizes also to discrete punctae
CC along the ciliary axoneme (PubMed:24089209).
CC {ECO:0000250|UniProtKB:Q9C0C7, ECO:0000269|PubMed:24089209}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1;
CC IsoId=A2AH22-1; Sequence=Displayed;
CC Name=2;
CC IsoId=A2AH22-2; Sequence=VSP_030658;
CC Name=3;
CC IsoId=A2AH22-3; Sequence=VSP_030661;
CC Name=4;
CC IsoId=A2AH22-4; Sequence=VSP_030659, VSP_030661;
CC Name=5;
CC IsoId=A2AH22-5; Sequence=VSP_030658, VSP_030659, VSP_030662,
CC VSP_030663;
CC Name=6;
CC IsoId=A2AH22-6; Sequence=VSP_030660;
CC Name=7;
CC IsoId=A2AH22-7; Sequence=VSP_030658, VSP_030659;
CC -!- TISSUE SPECIFICITY: Expressed throughout the brain, including midbrain
CC and striatum. {ECO:0000269|PubMed:21753002}.
CC -!- DEVELOPMENTAL STAGE: At 8.5 dpc, it is detected throughout the
CC neuroepithelium (PubMed:17589504). At 11.5 dpc, it is highly expressed
CC in the ventral-most part of the spinal cord, the encephalic vesicles,
CC the neural retina, the limbs and the dorsal root ganglia
CC (PubMed:17589504). Later, it is expressed in the entire developing
CC nervous system as well as in other tissues (PubMed:17589504). In brain,
CC strong expression is observed in the cortex, hippocampus and striatum
CC of postnatal brain (PubMed:17589504). {ECO:0000269|PubMed:17589504}.
CC -!- DOMAIN: The PxP motifs mediate interaction with the catalytic subunit
CC of protein phosphatase 2A (PPP2CA). {ECO:0000250|UniProtKB:Q9C0C7}.
CC -!- DOMAIN: The TQT motifs mediate interaction with the dynein light chain
CC proteins DYNLL1 and DYNLL2, tethering AMBRA1 to the cytoskeleton in
CC absence of autophagy. {ECO:0000250|UniProtKB:Q9C0C7}.
CC -!- DOMAIN: The LIR motif (LC3-interacting region) is required for the
CC interaction with the ATG8 family proteins GABARAP and MAP1LC3B.
CC {ECO:0000250|UniProtKB:Q9C0C7}.
CC -!- PTM: Phosphorylation at Ser-52 by MTOR inhibits its ability to regulate
CC autophagy and mediate ubiquitination of ULK1. Phosphorylation by ULK1
CC in response to autophagy induction abolishes interaction with DYNLL1
CC and DYNLL2, releasing AMBRA1 from the cytoskeletal docking site to
CC induce autophagosome nucleation. Phosphorylation by MTOR inhibits
CC interaction with PPP2CA and subsequent dephosphorylation of MYC.
CC Phosphorylation at Ser-1044 by CHUK/IKKA promotes its interaction with
CC ATG8 family proteins GABARAP and MAP1LC3B and its mitophagic activity.
CC {ECO:0000250|UniProtKB:Q9C0C7}.
CC -!- PTM: Ubiquitinated by RNF2 via 'Lys-48'-linkage in unstressed cells,
CC leading to its degradation by the proteasome (PubMed:24980959).
CC Induction of autophagy promotes stabilization via interaction with CUL4
CC (CUL4A or CUL4B) and DDB1. Upon prolonged starvation, ubiquitinated and
CC degraded, terminating the autophagy response (By similarity).
CC {ECO:0000250|UniProtKB:Q9C0C7, ECO:0000269|PubMed:24980959}.
CC -!- PTM: Undergoes proteolytic processing by caspase-6 (CASP6), caspase-7
CC (CASP7) and caspase-8 (CASP8) during apoptosis, resulting in the
CC dismantling of the autophagic machinery and the accomplishment of the
CC programmed cell death program. Also cleaved by calpains during
CC apoptosis, which mediate a complete proteolytic degradation.
CC {ECO:0000250|UniProtKB:Q9C0C7}.
CC -!- DISRUPTION PHENOTYPE: Embryonic lethality: mice display severe neural
CC tube defects associated with autophagy impairment, accumulation of
CC ubiquitinated proteins, unbalanced cell proliferation and excessive
CC apoptotic cell death (PubMed:17589504). Cells show an accumulation of
CC cyclin-D proteins (Ccnd1, Ccnd2 and Ccnd3), correlated with an increase
CC in retinoblastoma (RB) protein family phosphorylation, leading to
CC increased cell proliferation (PubMed:33854232, PubMed:33854235).
CC Conditional knockout mice lacking Ambra1 in the nervous system display
CC an increase in the volume of the cortex and the lateral ventricles,
CC associated with an enhanced rate of proliferation in the whole 13.5 dpc
CC brain and in the olfactory bulbs of the 18.5 dpc brain
CC (PubMed:33854232). Ambra1 deletion in a mouse lung cancer model leads
CC to increased cell proliferation, formation of replication stress and
CC chek1/Chk1 activation; cells are hypersensitive to chek1/Chk1
CC inhibition (PubMed:33854232). Impaired regulatory T-cells (Treg)
CC differentiation, leading to worsen disease pathogenesis in a mouse
CC model of multiple sclerosis (PubMed:30513302).
CC {ECO:0000269|PubMed:17589504, ECO:0000269|PubMed:30513302,
CC ECO:0000269|PubMed:33854232, ECO:0000269|PubMed:33854235}.
CC -!- SIMILARITY: Belongs to the WD repeat AMBRA1 family. {ECO:0000305}.
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DR EMBL; AK037516; BAC29823.1; -; mRNA.
DR EMBL; AK083596; BAC38965.1; -; mRNA.
DR EMBL; AK148887; BAE28691.1; -; mRNA.
DR EMBL; AK155513; BAE33303.1; -; mRNA.
DR EMBL; AK169280; BAE41038.1; -; mRNA.
DR EMBL; AL714023; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL731772; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK129433; BAC98243.1; -; mRNA.
DR CCDS; CCDS38179.1; -. [A2AH22-1]
DR CCDS; CCDS38180.1; -. [A2AH22-2]
DR RefSeq; NP_001074223.1; NM_001080754.1. [A2AH22-2]
DR RefSeq; NP_766257.3; NM_172669.3. [A2AH22-1]
DR RefSeq; XP_006499316.1; XM_006499253.1. [A2AH22-7]
DR AlphaFoldDB; A2AH22; -.
DR SMR; A2AH22; -.
DR BioGRID; 230728; 9.
DR IntAct; A2AH22; 4.
DR MINT; A2AH22; -.
DR STRING; 10090.ENSMUSP00000049258; -.
DR iPTMnet; A2AH22; -.
DR PhosphoSitePlus; A2AH22; -.
DR EPD; A2AH22; -.
DR MaxQB; A2AH22; -.
DR PaxDb; A2AH22; -.
DR PeptideAtlas; A2AH22; -.
DR PRIDE; A2AH22; -.
DR ProteomicsDB; 282078; -. [A2AH22-1]
DR ProteomicsDB; 282079; -. [A2AH22-2]
DR ProteomicsDB; 282080; -. [A2AH22-3]
DR ProteomicsDB; 282081; -. [A2AH22-4]
DR ProteomicsDB; 282082; -. [A2AH22-5]
DR ProteomicsDB; 282083; -. [A2AH22-6]
DR ProteomicsDB; 282084; -. [A2AH22-7]
DR Antibodypedia; 26331; 437 antibodies from 36 providers.
DR DNASU; 228361; -.
DR Ensembl; ENSMUST00000045699; ENSMUSP00000048898; ENSMUSG00000040506. [A2AH22-7]
DR Ensembl; ENSMUST00000045705; ENSMUSP00000049258; ENSMUSG00000040506. [A2AH22-1]
DR Ensembl; ENSMUST00000099712; ENSMUSP00000097299; ENSMUSG00000040506. [A2AH22-2]
DR Ensembl; ENSMUST00000111316; ENSMUSP00000106948; ENSMUSG00000040506. [A2AH22-6]
DR Ensembl; ENSMUST00000111317; ENSMUSP00000106949; ENSMUSG00000040506. [A2AH22-7]
DR GeneID; 228361; -.
DR KEGG; mmu:228361; -.
DR UCSC; uc008kwq.1; mouse. [A2AH22-1]
DR UCSC; uc008kwr.1; mouse. [A2AH22-4]
DR UCSC; uc008kws.1; mouse. [A2AH22-7]
DR UCSC; uc008kwt.1; mouse. [A2AH22-2]
DR CTD; 55626; -.
DR MGI; MGI:2443564; Ambra1.
DR VEuPathDB; HostDB:ENSMUSG00000040506; -.
DR eggNOG; KOG0266; Eukaryota.
DR GeneTree; ENSGT00390000016223; -.
DR HOGENOM; CLU_008882_0_0_1; -.
DR InParanoid; A2AH22; -.
DR OMA; GSENWFT; -.
DR OrthoDB; 488527at2759; -.
DR PhylomeDB; A2AH22; -.
DR TreeFam; TF328981; -.
DR Reactome; R-MMU-1632852; Macroautophagy.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 228361; 12 hits in 76 CRISPR screens.
DR ChiTaRS; Ambra1; mouse.
DR PRO; PR:A2AH22; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; A2AH22; protein.
DR Bgee; ENSMUSG00000040506; Expressed in animal zygote and 243 other tissues.
DR Genevisible; A2AH22; MM.
DR GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005930; C:axoneme; IDA:UniProtKB.
DR GO; GO:0080008; C:Cul4-RING E3 ubiquitin ligase complex; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; ISO:MGI.
DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0045335; C:phagocytic vesicle; IDA:MGI.
DR GO; GO:0051020; F:GTPase binding; ISO:MGI.
DR GO; GO:0019903; F:protein phosphatase binding; ISO:MGI.
DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; ISS:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0000045; P:autophagosome assembly; ISS:UniProtKB.
DR GO; GO:0006914; P:autophagy; IMP:MGI.
DR GO; GO:0000422; P:autophagy of mitochondrion; ISO:MGI.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0009267; P:cellular response to starvation; IEA:Ensembl.
DR GO; GO:0000423; P:mitophagy; ISO:MGI.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; ISO:MGI.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:MGI.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:MGI.
DR GO; GO:0021915; P:neural tube development; IMP:MGI.
DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProtKB.
DR GO; GO:1904544; P:positive regulation of free ubiquitin chain polymerization; ISS:UniProtKB.
DR GO; GO:1901526; P:positive regulation of mitophagy; ISS:UniProtKB.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISO:MGI.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; ISS:UniProtKB.
DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; IMP:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; ISS:UniProtKB.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0098780; P:response to mitochondrial depolarisation; ISO:MGI.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR036322; WD40_repeat_dom_sf.
DR SMART; SM00320; WD40; 3.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 1.
DR PROSITE; PS50082; WD_REPEATS_2; 1.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Autophagy; Cell cycle; Cell junction; Cytoplasm;
KW Cytoplasmic vesicle; Cytoskeleton; Developmental protein; Differentiation;
KW Endoplasmic reticulum; Isopeptide bond; Methylation; Mitochondrion;
KW Neurogenesis; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW Transcription; Transcription regulation; Ubl conjugation;
KW Ubl conjugation pathway; WD repeat.
FT CHAIN 1..1300
FT /note="Activating molecule in BECN1-regulated autophagy
FT protein 1"
FT /id="PRO_0000315704"
FT REPEAT 51..90
FT /note="WD 1"
FT REPEAT 93..133
FT /note="WD 2"
FT REPEAT 135..175
FT /note="WD 3"
FT REGION 1..22
FT /note="Interaction with DDB1"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT REGION 254..285
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 344..406
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 458..495
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 539..562
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 591..691
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 748..797
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1061..1080
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1113..1145
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1191..1300
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 275..281
FT /note="PxP motif 1"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOTIF 1044..1053
FT /note="LIR"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOTIF 1105..1107
FT /note="TQT motif 1"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOTIF 1117..1119
FT /note="TQT motif 2"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOTIF 1207..1213
FT /note="PxP motif 2"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT COMPBIAS 266..280
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 344..390
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 591..612
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 619..649
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 657..678
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 748..770
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1191..1217
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1231..1250
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1267..1282
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 483..484
FT /note="Cleavage; by caspase-6, caspase-7 and caspase-8"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 52
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 329
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 395
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 444
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 636
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 640
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 748
FT /note="Asymmetric dimethylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 1044
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT MOD_RES 1206
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9C0C7"
FT CROSSLNK 45
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:24980959"
FT VAR_SEQ 255..345
FT /note="Missing (in isoform 2, isoform 5 and isoform 7)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_030658"
FT VAR_SEQ 692..720
FT /note="Missing (in isoform 4, isoform 5 and isoform 7)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_030659"
FT VAR_SEQ 722..781
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_030660"
FT VAR_SEQ 782..1300
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_030661"
FT VAR_SEQ 1010..1016
FT /note="VSINSAR -> QRSTSLK (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_030662"
FT VAR_SEQ 1017..1300
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_030663"
FT MUTAGEN 2
FT /note="K->R: Does not affect ubiquitination by RNF2."
FT /evidence="ECO:0000269|PubMed:24980959"
FT MUTAGEN 7
FT /note="K->R: Does not affect ubiquitination by RNF2."
FT /evidence="ECO:0000269|PubMed:24980959"
FT MUTAGEN 36
FT /note="K->R: Does not affect ubiquitination by RNF2."
FT /evidence="ECO:0000269|PubMed:24980959"
FT MUTAGEN 41
FT /note="K->R: Does not affect ubiquitination by RNF2."
FT /evidence="ECO:0000269|PubMed:24980959"
FT MUTAGEN 45
FT /note="K->R: Abolished ubiquitination by RNF2."
FT /evidence="ECO:0000269|PubMed:24980959"
FT CONFLICT 111
FT /note="I -> T (in Ref. 1; BAE33303)"
FT /evidence="ECO:0000305"
FT CONFLICT 492
FT /note="N -> K (in Ref. 1; BAE33303)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1300 AA; 142879 MW; 081C4E14166B4985 CRC64;
MKVVPEKNAV RILWGRERGT RAMGAQRLLQ ELVEDKTRWM KWEGKRVELP DSPRSTFLLA
FSPDRTLLAS THVNHNIYIT EVKTGKCVHS LIGHRRTPWC VTFHPTISGL IASGCLDGEV
RIWDLHGGSE SWFTDSNNAI ASLAFHPTAQ LLLIATANEI HFWDWSRREP FAVVKTASEM
ERVRLVRFDP LGHYLLTAIV NPSNQQGDDE PEIPIDGTEL SHYRQRALLQ SQPVRRTPLL
HNFLHMLSSR SSGIQVGEQS TVQDSATPSP PPPPPQPSTE RPRTSAYIRL RQRVSYPTTV
ECCQHPGILC LCSRCAGTRV PSLLPHQDSV PPASARATTP SFSFVQTEPF HPPEQASSTQ
QDQGLLNRPS AFSTVQSSTA GNTLRNLSLG PTRRSLGGPL SSHPSRYHRE LAPGLTGSEW
TRTVLTLNSR SEVESMPPPR TSASSVSLLS VLRQQEGGSQ ASVYTSATEG RGFPSSGLAT
ESDGGNGSSQ NNSGSIRHEL QCDLRRFFLE YDRLQELDQS LSGETPQTQQ AQEMLNNNIE
SERPGPSHLP TPHSSENNSN LSRGHLNRCR ACHNLLTFNN DTLRWERTTP NYSSGEASSS
WHVSTTFEGM PPSGNQLPPL ERTEGQMPSS SRLELSSSAS SQEERTVGVA FNQETGHWER
IYTQSSRSGT VSQEALHQDM PEESSEEDSL RRRLLESSLI SLSRYDGAGS REHPIYPDPA
RLSPAAYYAQ RMIQYLSRRD SIRQRSMRYQ QNRLRSSTSS SSSDNQGPSV EGTDLEFEDF
EDNGDRSRHR APRNARMSAP SLGRFVPRRF LLPEYLPYAG IFHERGQPGL ATHSSVNRVL
AGAVIGDGQS AVASNIANTT YRLQWWDFTK FDLPEISNAS VNVLVQNCKI YNDASCDISA
DGQLLAAFIP SSQRGFPDEG ILAVYSLAPH NLGEMLYTKR FGPNAISVSL SPMGRYVMVG
LASRRILLHP STEHMVAQVF RLQQAHGGET SMRRVFNVLY PMPADQRRHV SINSARWLPE
PGLGLAYGTN KGDLVICRPE ALNSGIEYYW DQLSETVFTV HSSSRSSERP GTSRATWRTD
RDMGLMNAIG LQPRNPTTSV TSQGTQTLAL QLQNAETQTE REEEEPGAAS SGPGEGEGSE
YGGSGEDALS RIQRLMAEGG MTAVVQREQS TTMASMGGFG NNIIVSHRIH RSSQTGTESG
AARTSSPQPS TSRGLPSEPG QLAERALSPR TASWDQPSTS GRELPQPALS SSSPVPIPVP
LASNEGPTMH CNVTNNSHLP EGDGSNRGEA AGPSGEPQNR
