ID AP4M1_HUMAN Reviewed; 453 AA. AC O00189; D6W5U1; Q8WV65; Q9UHK9; DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot. DT 17-APR-2007, sequence version 2. DT 27-MAR-2024, entry version 184. DE RecName: Full=AP-4 complex subunit mu-1 {ECO:0000305}; DE AltName: Full=AP-4 adaptor complex mu subunit; DE AltName: Full=Adaptor-related protein complex 4 subunit mu-1; DE AltName: Full=Mu subunit of AP-4; DE AltName: Full=Mu-adaptin-related protein 2; DE Short=mu-ARP2; DE AltName: Full=Mu4-adaptin; DE Short=mu4; GN Name=AP4M1 {ECO:0000312|HGNC:HGNC:574}; Synonyms=MUARP2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=9013859; DOI=10.1016/s0014-5793(96)01500-1; RA Wang X., Kilimann M.W.; RT "Identification of two new mu-adaptin-related proteins, mu-ARP1 and mu- RT ARP2."; RL FEBS Lett. 402:57-61(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBUNIT. RC TISSUE=Brain; RX PubMed=10436028; DOI=10.1091/mbc.10.8.2787; RA Hirst J., Bright N.A., Rous B., Robinson M.S.; RT "Characterization of a fourth adaptor-related protein complex."; RL Mol. Biol. Cell 10:2787-2802(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH LAMP2, AND RP SUBCELLULAR LOCATION. RC TISSUE=Spleen; RX PubMed=11139587; DOI=10.1074/jbc.m010591200; RA Aguilar R.C., Boehm M., Gorshkova I., Crouch R.J., Tomita K., Saito T., RA Ohno H., Bonifacino J.S.; RT "Signal-binding specificity of the mu4 subunit of the adaptor protein RT complex, AP-4."; RL J. Biol. Chem. 276:13145-13152(2001). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, AND SUBUNIT. RX PubMed=10066790; DOI=10.1074/jbc.274.11.7278; RA Dell'Angelica E.C., Mullins C., Bonifacino J.S.; RT "AP-4, a novel protein complex related to clathrin adaptors."; RL J. Biol. Chem. 274:7278-7285(1999). RN [7] RP INVOLVEMENT IN SPG50. RX PubMed=19559397; DOI=10.1016/j.ajhg.2009.06.004; RA Verkerk A.J., Schot R., Dumee B., Schellekens K., Swagemakers S., RA Bertoli-Avella A.M., Lequin M.H., Dudink J., Govaert P., van Zwol A.L., RA Hirst J., Wessels M.W., Catsman-Berrevoets C., Verheijen F.W., RA de Graaff E., de Coo I.F., Kros J.M., Willemsen R., Willems P.J., RA van der Spek P.J., Mancini G.M.; RT "Mutation in the AP4M1 gene provides a model for neuroaxonal injury in RT cerebral palsy."; RL Am. J. Hum. Genet. 85:40-52(2009). RN [8] RP FUNCTION, AND SUBUNIT. RX PubMed=11802162; DOI=10.1038/ncb745; RA Simmen T., Hoening S., Icking A., Tikkanen R., Hunziker W.; RT "AP-4 binds basolateral signals and participates in basolateral sorting in RT epithelial MDCK cells."; RL Nat. Cell Biol. 4:154-159(2002). RN [9] RP FUNCTION, AND INTERACTION WITH NAGPA. RX PubMed=26544806; DOI=10.1016/j.ajhg.2015.10.007; RA Raza M.H., Mattera R., Morell R., Sainz E., Rahn R., Gutierrez J., RA Paris E., Root J., Solomon B., Brewer C., Basra M.A., Khan S., RA Riazuddin S., Braun A., Bonifacino J.S., Drayna D.; RT "Association between rare variants in AP4E1, a component of intracellular RT trafficking, and persistent stuttering."; RL Am. J. Hum. Genet. 97:715-725(2015). RN [10] RP INTERACTION WITH ATG9A, AND SUBCELLULAR LOCATION. RX PubMed=29180427; DOI=10.1073/pnas.1717327114; RA Mattera R., Park S.Y., De Pace R., Guardia C.M., Bonifacino J.S.; RT "AP-4 mediates export of ATG9A from the trans-Golgi network to promote RT autophagosome formation."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E10697-E10706(2017). RN [11] RP INTERACTION WITH HOOK1 AND HOOK2, AND SUBCELLULAR LOCATION. RX PubMed=32073997; DOI=10.1091/mbc.e19-11-0658; RA Mattera R., Williamson C.D., Ren X., Bonifacino J.S.; RT "The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear RT distribution of AP-4 and its cargo ATG9A."; RL Mol. Biol. Cell 31:963-979(2020). RN [12] RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 160-453 IN COMPLEX WITH APP RP PEPTIDE, FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF PHE-255 AND RP ARG-283, AND SUBUNIT. RX PubMed=20230749; DOI=10.1016/j.devcel.2010.01.015; RA Burgos P.V., Mardones G.A., Rojas A.L., daSilva L.L., Prabhu Y., RA Hurley J.H., Bonifacino J.S.; RT "Sorting of the Alzheimer's disease amyloid precursor protein mediated by RT the AP-4 complex."; RL Dev. Cell 18:425-436(2010). CC -!- FUNCTION: Component of the adaptor protein complex 4 (AP-4). Adaptor CC protein complexes are vesicle coat components involved both in vesicle CC formation and cargo selection. They control the vesicular transport of CC proteins in different trafficking pathways (PubMed:10436028, CC PubMed:11139587, PubMed:10066790, PubMed:11802162, PubMed:20230749). CC AP-4 forms a non clathrin-associated coat on vesicles departing the CC trans-Golgi network (TGN) and may be involved in the targeting of CC proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal CC system (PubMed:11139587, PubMed:20230749). It is also involved in CC protein sorting to the basolateral membrane in epithelial cells and the CC proper asymmetric localization of somatodendritic proteins in neurons CC (By similarity). Within AP-4, the mu-type subunit AP4M1 is directly CC involved in the recognition and binding of tyrosine-based sorting CC signals found in the cytoplasmic part of cargos (PubMed:10436028, CC PubMed:11139587, PubMed:26544806, PubMed:20230749). The adaptor protein CC complex 4 (AP-4) may also recognize other types of sorting signal (By CC similarity). {ECO:0000250|UniProtKB:E2RED8, CC ECO:0000250|UniProtKB:Q2PWT8, ECO:0000250|UniProtKB:Q9JKC7, CC ECO:0000269|PubMed:10066790, ECO:0000269|PubMed:10436028, CC ECO:0000269|PubMed:11139587, ECO:0000269|PubMed:11802162, CC ECO:0000269|PubMed:20230749, ECO:0000269|PubMed:26544806}. CC -!- SUBUNIT: Adaptor protein complex 4 (AP-4) is a heterotetramer composed CC of two large adaptins (epsilon-type subunit AP4E1 and beta-type subunit CC AP4B1), a medium adaptin (mu-type subunit AP4M1) and a small adaptin CC (sigma-type AP4S1) (PubMed:10436028, PubMed:10066790, PubMed:11802162). CC Interacts with tyrosine-based sorting signals on the cytoplasmic tail CC of cargo proteins such as APP, ATG9A, LAMP2 and NAGPA (PubMed:11139587, CC PubMed:26544806, PubMed:29180427, PubMed:20230749). Interacts with the CC C-terminal domain of GRID2 (By similarity). Interacts with GRIA1 and CC GRIA2; the interaction is indirect via CACNG3 (By similarity). CC Interacts with CACNG3; CACNG3 associates GRIA1 and GRIA2 with the CC adaptor protein complex 4 (AP-4) to target them to the somatodendritic CC compartment of neurons (By similarity). Interacts with HOOK1 and HOOK2; CC the interactions are direct, mediate the interaction between FTS-Hook- CC FHIP (FHF) complex and AP-4 and the perinuclear distribution of AP-4 CC (PubMed:32073997). {ECO:0000250|UniProtKB:Q2PWT8, CC ECO:0000250|UniProtKB:Q9JKC7, ECO:0000269|PubMed:10066790, CC ECO:0000269|PubMed:10436028, ECO:0000269|PubMed:11139587, CC ECO:0000269|PubMed:11802162, ECO:0000269|PubMed:20230749, CC ECO:0000269|PubMed:26544806, ECO:0000269|PubMed:29180427, CC ECO:0000269|PubMed:32073997}. CC -!- INTERACTION: CC O00189; P49354: FNTA; NbExp=3; IntAct=EBI-3914106, EBI-602336; CC O00189; Q9UJC3: HOOK1; NbExp=4; IntAct=EBI-3914106, EBI-746704; CC O00189; Q96N21: TEPSIN; NbExp=3; IntAct=EBI-3914106, EBI-11139477; CC O00189; Q96K76: USP47; NbExp=3; IntAct=EBI-3914106, EBI-2514143; CC O00189; Q96K76-3: USP47; NbExp=3; IntAct=EBI-3914106, EBI-12313025; CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane CC {ECO:0000269|PubMed:20230749, ECO:0000269|PubMed:29180427, CC ECO:0000269|PubMed:32073997}; Peripheral membrane protein CC {ECO:0000305|PubMed:32073997}. Early endosome CC {ECO:0000269|PubMed:20230749}. Note=Found in soma and dendritic shafts CC of neuronal cells. {ECO:0000250|UniProtKB:Q2PWT8}. CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in testis and lowly CC expressed in brain and lung. {ECO:0000269|PubMed:9013859}. CC -!- DISEASE: Spastic paraplegia 50, autosomal recessive (SPG50) CC [MIM:612936]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. SPG50 affected CC individuals present postnatally with early infantile hypotonia, delayed CC psychomotor development, strabismus, lack of independent walking and CC severe intellectual disability. They develop progressive spasticity of CC all limbs with generalized hypertonia, hyperreflexia, and extensor CC plantar responses by the end of the first year of life. Speech is CC absent or limited. Pseudobulbar signs, such as drooling, stereotypic CC laughter, and exaggerated jaw jerk, are part of the clinical picture. CC {ECO:0000269|PubMed:19559397}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the adaptor complexes medium subunit family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y08387; CAA69667.1; -; mRNA. DR EMBL; AF155158; AAD43328.1; -; mRNA. DR EMBL; AF020796; AAD25869.1; -; mRNA. DR EMBL; CH471091; EAW76594.1; -; Genomic_DNA. DR EMBL; CH471091; EAW76597.1; -; Genomic_DNA. DR EMBL; BC018705; AAH18705.1; -; mRNA. DR CCDS; CCDS5685.1; -. DR RefSeq; NP_004713.2; NM_004722.3. DR PDB; 3L81; X-ray; 1.60 A; A=160-453. DR PDB; 4MDR; X-ray; 1.85 A; A=160-453. DR PDBsum; 3L81; -. DR PDBsum; 4MDR; -. DR AlphaFoldDB; O00189; -. DR SMR; O00189; -. DR BioGRID; 114616; 50. DR ComplexPortal; CPX-5151; AP-4 Adaptor complex. DR CORUM; O00189; -. DR IntAct; O00189; 36. DR MINT; O00189; -. DR STRING; 9606.ENSP00000403663; -. DR TCDB; 9.B.278.1.5; the organellar-targeting adaptor protein complex (o-apc) family. DR iPTMnet; O00189; -. DR PhosphoSitePlus; O00189; -. DR BioMuta; AP4M1; -. DR EPD; O00189; -. DR jPOST; O00189; -. DR MassIVE; O00189; -. DR MaxQB; O00189; -. DR PaxDb; 9606-ENSP00000352603; -. DR PeptideAtlas; O00189; -. DR ProteomicsDB; 47769; -. DR Pumba; O00189; -. DR TopDownProteomics; O00189; -. DR Antibodypedia; 30540; 183 antibodies from 25 providers. DR DNASU; 9179; -. DR Ensembl; ENST00000359593.9; ENSP00000352603.4; ENSG00000221838.10. DR Ensembl; ENST00000421755.5; ENSP00000412185.1; ENSG00000221838.10. DR GeneID; 9179; -. DR KEGG; hsa:9179; -. DR MANE-Select; ENST00000359593.9; ENSP00000352603.4; NM_004722.4; NP_004713.2. DR UCSC; uc003utb.5; human. DR AGR; HGNC:574; -. DR CTD; 9179; -. DR DisGeNET; 9179; -. DR GeneCards; AP4M1; -. DR GeneReviews; AP4M1; -. DR HGNC; HGNC:574; AP4M1. DR HPA; ENSG00000221838; Low tissue specificity. DR MalaCards; AP4M1; -. DR MIM; 602296; gene. DR MIM; 612936; phenotype. DR neXtProt; NX_O00189; -. DR OpenTargets; ENSG00000221838; -. DR Orphanet; 280763; Severe intellectual disability and progressive spastic paraplegia. DR PharmGKB; PA24866; -. DR VEuPathDB; HostDB:ENSG00000221838; -. DR eggNOG; KOG0937; Eukaryota. DR GeneTree; ENSGT00940000159929; -. DR InParanoid; O00189; -. DR OMA; DYGYIQN; -. DR OrthoDB; 5353102at2759; -. DR PhylomeDB; O00189; -. DR TreeFam; TF329745; -. DR PathwayCommons; O00189; -. DR Reactome; R-HSA-432720; Lysosome Vesicle Biogenesis. DR SignaLink; O00189; -. DR BioGRID-ORCS; 9179; 11 hits in 1159 CRISPR screens. DR ChiTaRS; AP4M1; human. DR EvolutionaryTrace; O00189; -. DR GeneWiki; AP4M1; -. DR GenomeRNAi; 9179; -. DR Pharos; O00189; Tbio. DR PRO; PR:O00189; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; O00189; Protein. DR Bgee; ENSG00000221838; Expressed in left testis and 111 other cell types or tissues. DR ExpressionAtlas; O00189; baseline and differential. DR GO; GO:0030124; C:AP-4 adaptor complex; IDA:UniProtKB. DR GO; GO:0030131; C:clathrin adaptor complex; IEA:InterPro. DR GO; GO:0031410; C:cytoplasmic vesicle; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IEA:GOC. DR GO; GO:0005769; C:early endosome; ISS:UniProtKB. DR GO; GO:0031904; C:endosome lumen; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB. DR GO; GO:0032588; C:trans-Golgi network membrane; TAS:Reactome. DR GO; GO:0019904; F:protein domain specific binding; IDA:UniProtKB. DR GO; GO:0008320; F:protein transmembrane transporter activity; TAS:Reactome. DR GO; GO:0000045; P:autophagosome assembly; IMP:UniProtKB. DR GO; GO:0006895; P:Golgi to endosome transport; IMP:UniProtKB. DR GO; GO:0090160; P:Golgi to lysosome transport; IDA:UniProtKB. DR GO; GO:0006886; P:intracellular protein transport; IMP:UniProtKB. DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; TAS:Reactome. DR GO; GO:0008104; P:protein localization; ISS:UniProtKB. DR GO; GO:1903361; P:protein localization to basolateral plasma membrane; ISS:UniProtKB. DR GO; GO:0006605; P:protein targeting; IDA:UniProtKB. DR GO; GO:0006622; P:protein targeting to lysosome; IDA:UniProtKB. DR GO; GO:0016192; P:vesicle-mediated transport; NAS:ComplexPortal. DR CDD; cd09253; AP-4_Mu4_Cterm; 1. DR CDD; cd14838; AP4_Mu_N; 1. DR Gene3D; 3.30.450.60; -; 1. DR Gene3D; 2.60.40.1170; Mu homology domain, subdomain B; 2. DR InterPro; IPR036168; AP2_Mu_C_sf. DR InterPro; IPR022775; AP_mu_sigma_su. DR InterPro; IPR001392; Clathrin_mu. DR InterPro; IPR018240; Clathrin_mu_CS. DR InterPro; IPR011012; Longin-like_dom_sf. DR InterPro; IPR028565; MHD. DR PANTHER; PTHR10529; AP COMPLEX SUBUNIT MU; 1. DR PANTHER; PTHR10529:SF270; AP-4 COMPLEX SUBUNIT MU-1; 1. DR Pfam; PF00928; Adap_comp_sub; 1. DR Pfam; PF01217; Clat_adaptor_s; 1. DR PIRSF; PIRSF005992; Clathrin_mu; 1. DR PRINTS; PR00314; CLATHRINADPT. DR SUPFAM; SSF49447; Second domain of Mu2 adaptin subunit (ap50) of ap2 adaptor; 1. DR SUPFAM; SSF64356; SNARE-like; 1. DR PROSITE; PS00991; CLAT_ADAPTOR_M_2; 1. DR PROSITE; PS51072; MHD; 1. DR Genevisible; O00189; HS. PE 1: Evidence at protein level; KW 3D-structure; Endosome; Golgi apparatus; Hereditary spastic paraplegia; KW Membrane; Neurodegeneration; Protein transport; Reference proteome; KW Transport. FT CHAIN 1..453 FT /note="AP-4 complex subunit mu-1" FT /id="PRO_0000193787" FT DOMAIN 184..452 FT /note="MHD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00404" FT MUTAGEN 255 FT /note="F->A: Abolishes interaction with APP." FT /evidence="ECO:0000269|PubMed:20230749" FT MUTAGEN 283 FT /note="R->D: Strongly reduced interaction with APP." FT /evidence="ECO:0000269|PubMed:20230749" FT CONFLICT 338 FT /note="R -> G (in Ref. 2; AAD43328)" FT /evidence="ECO:0000305" FT CONFLICT 345 FT /note="Q -> R (in Ref. 1; CAA69667 and 3; AAD25869)" FT /evidence="ECO:0000305" FT CONFLICT 400 FT /note="L -> M (in Ref. 2; AAD43328)" FT /evidence="ECO:0000305" FT CONFLICT 417 FT /note="S -> C (in Ref. 2; AAD43328)" FT /evidence="ECO:0000305" FT STRAND 186..199 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 205..218 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 225..230 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 235..237 FT /evidence="ECO:0007829|PDB:3L81" FT TURN 240..242 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 246..256 FT /evidence="ECO:0007829|PDB:3L81" FT HELIX 264..267 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 269..272 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 276..286 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 295..304 FT /evidence="ECO:0007829|PDB:3L81" FT TURN 306..308 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 309..319 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 326..335 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 341..349 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 353..357 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 360..365 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 373..381 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 405..412 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 421..427 FT /evidence="ECO:0007829|PDB:3L81" FT STRAND 437..451 FT /evidence="ECO:0007829|PDB:3L81" SQ SEQUENCE 453 AA; 49977 MW; AE3DCA8C5AED08B7 CRC64; MISQFFILSS KGDPLIYKDF RGDSGGRDVA ELFYRKLTGL PGDESPVVMH HHGRHFIHIR HSGLYLVVTT SENVSPFSLL ELLSRLATLL GDYCGSLGEG TISRNVALVY ELLDEVLDYG YVQTTSTEML RNFIQTEAVV SKPFSLFDLS SVGLFGAETQ QSKVAPSSAA SRPVLSSRSD QSQKNEVFLD VVERLSVLIA SNGSLLKVDV QGEIRLKSFL PSGSEMRIGL TEEFCVGKSE LRGYGPGIRV DEVSFHSSVN LDEFESHRIL RLQPPQGELT VMRYQLSDDL PSPLPFRLFP SVQWDRGSGR LQVYLKLRCD LLSKSQALNV RLHLPLPRGV VSLSQELSSP EQKAELAEGA LRWDLPRVQG GSQLSGLFQM DVPGPPGPPS HGLSTSASPL GLGPASLSFE LPRHTCSGLQ VRFLRLAFRP CGNANPHKWV RHLSHSDAYV IRI //