ID PEX6_HUMAN Reviewed; 980 AA. AC Q13608; Q5T8W1; Q8WYQ0; Q8WYQ1; Q8WYQ2; Q99476; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 08-DEC-2000, sequence version 2. DT 28-JUN-2023, entry version 196. DE RecName: Full=Peroxisomal ATPase PEX6 {ECO:0000305}; DE EC=3.6.4.- {ECO:0000269|PubMed:16854980}; DE AltName: Full=Peroxin-6 {ECO:0000305}; DE AltName: Full=Peroxisomal biogenesis factor 6 {ECO:0000305}; DE AltName: Full=Peroxisomal-type ATPase 1; DE AltName: Full=Peroxisome assembly factor 2 {ECO:0000303|PubMed:8670792}; DE Short=PAF-2 {ECO:0000303|PubMed:8670792}; GN Name=PEX6 {ECO:0000303|PubMed:10408779, ECO:0000312|HGNC:HGNC:8859}; GN Synonyms=PXAAA1 {ECO:0000303|PubMed:8670792}; 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 [GENOMIC DNA], AND INVOLVEMENT IN PBD4A. RX PubMed=8670792; DOI=10.1002/j.1460-2075.1996.tb00654.x; RA Yahraus T., Braverman N., Dodt G., Kalish J.E., Morrell J.C., Moser H.W., RA Valle D., Gould S.J.; RT "The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a RT cytoplasmic ATPase required for stability of the PTS1 receptor."; RL EMBO J. 15:2914-2923(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8940266; RA Fukuda S., Shimozawa N., Suzuki Y., Zhang Z., Tomatsu S., Tsukamoto T., RA Hashiguchi N., Osumi T., Masuno M., Imaizumi K., Kuroki Y., Fujiki Y., RA Orii T., Kondo N.; RT "Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C RT peroxisome biogenesis disorder in humans."; RL Am. J. Hum. Genet. 59:1210-1220(1996). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PBD4A GLN-812 AND TRP-812. RX PubMed=10408779; RX DOI=10.1002/(sici)1098-1004(1999)13:6<487::aid-humu9>3.0.co;2-t; RA Zhang Z., Suzuki Y., Shimozawa N., Fukuda S., Imamura A., Tsukamoto T., RA Osumi T., Fujiki Y., Orii T., Wanders R.J.A., Barth P.G., Moser H.W., RA Paton B.C., Besley G.T., Kondo N.; RT "Genomic structure and identification of 11 novel mutations of the PEX6 RT 'peroxisome assembly factor-2' gene in patients with peroxisome biogenesis RT disorders."; RL Hum. Mutat. 13:487-496(1999). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), SUBCELLULAR LOCATION, RP VARIANT GLN-939, INVOLVEMENT IN PBD4B, AND ALTERNATIVE SPLICING. RX PubMed=11355018; DOI=10.1007/s100380170078; RA Matsumoto N., Tamura S., Moser A., Moser H.W., Braverman N., Suzuki Y., RA Shimozawa N., Kondo N., Fujiki Y.; RT "The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of RT complementation group 6."; RL J. Hum. Genet. 46:273-277(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Synovium; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Colon; 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 [9] RP INTERACTION WITH PEX26 AND PEX1. RX PubMed=12717447; DOI=10.1038/ncb982; RA Matsumoto N., Tamura S., Fujiki Y.; RT "The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA ATPase RT complexes to peroxisomes."; RL Nat. Cell Biol. 5:454-460(2003). RN [10] RP FUNCTION. RX PubMed=16314507; DOI=10.1128/mcb.25.24.10822-10832.2005; RA Miyata N., Fujiki Y.; RT "Shuttling mechanism of peroxisome targeting signal type 1 receptor Pex5: RT ATP-independent import and ATP-dependent export."; RL Mol. Cell. Biol. 25:10822-10832(2005). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH PEX1 RP AND PEX26, AND MUTAGENESIS OF LYS-476; ASP-532; LYS-750 AND ASP-803. RX PubMed=16854980; DOI=10.1074/jbc.m605159200; RA Tamura S., Yasutake S., Matsumoto N., Fujiki Y.; RT "Dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and RT their membrane receptor Pex26p."; RL J. Biol. Chem. 281:27693-27704(2006). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PEX1 AND PEX26, AND RP MUTAGENESIS OF LYS-476; ASP-532; LYS-750 AND ASP-803. RX PubMed=21362118; DOI=10.1111/j.1600-0854.2011.01182.x; RA Nashiro C., Kashiwagi A., Matsuzaki T., Tamura S., Fujiki Y.; RT "Recruiting mechanism of the AAA peroxins, Pex1p and Pex6p, to Pex26p on RT the peroxisomal membrane."; RL Traffic 12:774-788(2011). RN [13] RP FUNCTION. RX PubMed=29884772; DOI=10.1074/jbc.ra118.003669; RA Pedrosa A.G., Francisco T., Bicho D., Dias A.F., Barros-Barbosa A., RA Hagmann V., Dodt G., Rodrigues T.A., Azevedo J.E.; RT "Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and RT PEX6 and is unfolded during its dislocation into the cytosol."; RL J. Biol. Chem. 293:11553-11563(2018). RN [14] RP INVOLVEMENT IN PBD-CG4, INVOLVEMENT IN HMLR2, VARIANTS PBD-CG4 THR-849; RP GLN-860 AND TRP-860, VARIANTS HMLR2 LEU-274 AND GLN-601, AND VARIANTS RP PRO-79; VAL-809; ILE-882; SER-924 AND GLN-939. RX PubMed=19105186; DOI=10.1002/humu.20932; RA Yik W.Y., Steinberg S.J., Moser A.B., Moser H.W., Hacia J.G.; RT "Identification of novel mutations and sequence variation in the Zellweger RT syndrome spectrum of peroxisome biogenesis disorders."; RL Hum. Mutat. 30:E467-E480(2009). RN [15] RP INVOLVEMENT IN PBD-CG4, AND VARIANT PBD-CG4 PRO-534. RX PubMed=21937992; DOI=10.1038/nature10423; RA Najmabadi H., Hu H., Garshasbi M., Zemojtel T., Abedini S.S., Chen W., RA Hosseini M., Behjati F., Haas S., Jamali P., Zecha A., Mohseni M., RA Puettmann L., Vahid L.N., Jensen C., Moheb L.A., Bienek M., Larti F., RA Mueller I., Weissmann R., Darvish H., Wrogemann K., Hadavi V., RA Lipkowitz B., Esmaeeli-Nieh S., Wieczorek D., Kariminejad R., RA Firouzabadi S.G., Cohen M., Fattahi Z., Rost I., Mojahedi F., Hertzberg C., RA Dehghan A., Rajab A., Banavandi M.J., Hoffer J., Falah M., Musante L., RA Kalscheuer V., Ullmann R., Kuss A.W., Tzschach A., Kahrizi K., Ropers H.H.; RT "Deep sequencing reveals 50 novel genes for recessive cognitive RT disorders."; RL Nature 478:57-63(2011). RN [16] RP INTERACTION WITH ZFAND6. RX PubMed=21980954; DOI=10.1111/j.1600-0854.2011.01298.x; RA Miyata N., Okumoto K., Mukai S., Noguchi M., Fujiki Y.; RT "AWP1/ZFAND6 functions in Pex5 export by interacting with cys- RT monoubiquitinated Pex5 and Pex6 AAA ATPase."; RL Traffic 13:168-183(2012). RN [17] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-119, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Colon carcinoma; 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 [18] RP INVOLVEMENT IN PBD4A. RX PubMed=17041890; DOI=10.1002/humu.9462; RA Krause C., Rosewich H., Thanos M., Gaertner J.; RT "Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 RT in Zellweger spectrum patients."; RL Hum. Mutat. 27:1157-1157(2006). RN [19] RP INVOLVEMENT IN HMLR2, VARIANTS HMLR2 LEU-274; GLN-601 AND TRP-644, AND RP CHARACTERIZATION OF VARIANTS HMLR2 LEU-274; GLN-601 AND TRP-644. RX PubMed=26387595; DOI=10.1016/j.ajhg.2015.08.011; RA Ratbi I., Falkenberg K.D., Sommen M., Al-Sheqaih N., Guaoua S., RA Vandeweyer G., Urquhart J.E., Chandler K.E., Williams S.G., Roberts N.A., RA El Alloussi M., Black G.C., Ferdinandusse S., Ramdi H., Heimler A., RA Fryer A., Lynch S.A., Cooper N., Ong K.R., Smith C.E., Inglehearn C.F., RA Mighell A.J., Elcock C., Poulter J.A., Tischkowitz M., Davies S.J., RA Sefiani A., Mironov A.A., Newman W.G., Waterham H.R., Van Camp G.; RT "Heimler syndrome is caused by hypomorphic mutations in the peroxisome- RT biogenesis genes PEX1 and PEX6."; RL Am. J. Hum. Genet. 97:535-545(2015). RN [20] RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND VARIANT PBD-CG4 VAL-413. RX PubMed=26593283; DOI=10.1002/humu.22934; RA Zaki M.S., Heller R., Thoenes M., Nuernberg G., Stern-Schneider G., RA Nuernberg P., Karnati S., Swan D., Fateen E., Nagel-Wolfrum K., RA Mostafa M.I., Thiele H., Wolfrum U., Baumgart-Vogt E., Bolz H.J.; RT "PEX6 is expressed in photoreceptor cilia and mutated in deafblindness with RT enamel dysplasia and microcephaly."; RL Hum. Mutat. 37:170-174(2016). RN [21] RP VARIANTS HMLR2 GLY-92; LEU-99; LEU-218; ILE-572; GLN-601 AND PHE-905. RX PubMed=27302843; DOI=10.1038/ejhg.2016.62; RA Smith C.E., Poulter J.A., Levin A.V., Capasso J.E., Price S., Ben-Yosef T., RA Sharony R., Newman W.G., Shore R.C., Brookes S.J., Mighell A.J., RA Inglehearn C.F.; RT "Spectrum of PEX1 and PEX6 variants in Heimler syndrome."; RL Eur. J. Hum. Genet. 24:1565-1571(2016). CC -!- FUNCTION: Component of the PEX1-PEX6 AAA ATPase complex, a protein CC dislocase complex that mediates the ATP-dependent extraction of the CC PEX5 receptor from peroxisomal membranes, an essential step for PEX5 CC recycling (PubMed:16314507, PubMed:16854980, PubMed:21362118, CC PubMed:29884772). Specifically recognizes PEX5 monoubiquitinated at CC 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2- CC PEX10-PEX12 retrotranslocation channel (PubMed:29884772). Extraction by CC the PEX1-PEX6 AAA ATPase complex is accompanied by unfolding of the TPR CC repeats and release of bound cargo from PEX5 (PubMed:29884772). CC {ECO:0000269|PubMed:16314507, ECO:0000269|PubMed:16854980, CC ECO:0000269|PubMed:21362118, ECO:0000269|PubMed:29884772}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; CC Evidence={ECO:0000269|PubMed:16854980}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13066; CC Evidence={ECO:0000269|PubMed:16854980}; CC -!- SUBUNIT: Interacts with PEX1; forming the PEX1-PEX6 AAA ATPase complex, CC which is composed of a heterohexamer formed by a trimer of PEX1-PEX6 CC dimers (PubMed:12717447, PubMed:16854980, PubMed:21362118). Interacts CC with PEX26; interaction is direct and promotes recruitment to CC peroxisomal membranes (PubMed:12717447, PubMed:16854980). Interacts CC with ZFAND6 (PubMed:21980954). {ECO:0000269|PubMed:12717447, CC ECO:0000269|PubMed:16854980, ECO:0000269|PubMed:21362118, CC ECO:0000269|PubMed:21980954}. CC -!- INTERACTION: CC Q13608; O43933: PEX1; NbExp=2; IntAct=EBI-988581, EBI-988601; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:16854980}. CC Peroxisome membrane {ECO:0000269|PubMed:11355018, CC ECO:0000269|PubMed:12717447, ECO:0000269|PubMed:16854980, CC ECO:0000269|PubMed:21362118}. Cell projection, cilium, photoreceptor CC outer segment {ECO:0000269|PubMed:26593283}. Note=Associated with CC peroxisomal membranes; anchored by PEX26 to peroxisome membranes CC (PubMed:12717447, PubMed:16854980). Localized at the base of the outer CC segment of photoreceptor cells (PubMed:26593283). CC {ECO:0000269|PubMed:12717447, ECO:0000269|PubMed:16854980, CC ECO:0000269|PubMed:26593283}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q13608-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13608-2; Sequence=VSP_057138, VSP_057139; CC Name=3; CC IsoId=Q13608-3; Sequence=VSP_057137; CC -!- TISSUE SPECIFICITY: Expressed in the retina, at higher levels in the CC photoreceptor layer at the joint between the outer and inner segments. CC {ECO:0000269|PubMed:26593283}. CC -!- DISEASE: Peroxisome biogenesis disorder complementation group 4 (PBD- CC CG4) [MIM:614862]: A peroxisomal disorder arising from a failure of CC protein import into the peroxisomal membrane or matrix. The peroxisome CC biogenesis disorders (PBD group) are genetically heterogeneous with at CC least 14 distinct genetic groups as concluded from complementation CC studies. Include disorders are: Zellweger syndrome (ZWS), neonatal CC adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and CC classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and CC IRD are distinct from RCDP and constitute a clinical continuum of CC overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS). CC {ECO:0000269|PubMed:19105186, ECO:0000269|PubMed:21937992, CC ECO:0000269|PubMed:26593283}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Peroxisome biogenesis disorder 4A (PBD4A) [MIM:614862]: A CC fatal peroxisome biogenesis disorder belonging to the Zellweger disease CC spectrum and clinically characterized by severe neurologic dysfunction CC with profound psychomotor retardation, severe hypotonia and neonatal CC seizures, craniofacial abnormalities, liver dysfunction, and CC biochemically by the absence of peroxisomes. Additional features CC include cardiovascular and skeletal defects, renal cysts, ocular CC abnormalities, and hearing impairment. Most severely affected CC individuals with the classic form of the disease (classic Zellweger CC syndrome) die within the first year of life. CC {ECO:0000269|PubMed:10408779, ECO:0000269|PubMed:17041890, CC ECO:0000269|PubMed:8670792}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Peroxisome biogenesis disorder 4B (PBD4B) [MIM:614863]: A CC peroxisome biogenesis disorder that includes neonatal CC adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two CC milder manifestations of the Zellweger disease spectrum. The clinical CC course of patients with the NALD and IRD presentation is variable and CC may include developmental delay, hypotonia, liver dysfunction, CC sensorineural hearing loss, retinal dystrophy and vision impairment. CC Children with the NALD presentation may reach their teens, while CC patients with the IRD presentation may reach adulthood. The clinical CC conditions are often slowly progressive in particular with respect to CC loss of hearing and vision. The biochemical abnormalities include CC accumulation of phytanic acid, very long chain fatty acids (VLCFA), CC di- and trihydroxycholestanoic acid and pipecolic acid. CC {ECO:0000269|PubMed:11355018}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Heimler syndrome 2 (HMLR2) [MIM:616617]: A form of Heimler CC syndrome, a very mild peroxisome biogenesis disorder characterized by CC sensorineural hearing loss, amelogenesis imperfecta resulting in enamel CC hyoplasia of the secondary dentition, nail defects, and occasional or CC late-onset retinal pigmentation abnormalities. CC {ECO:0000269|PubMed:19105186, ECO:0000269|PubMed:26387595, CC ECO:0000269|PubMed:27302843}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the AAA ATPase family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=dbPEX, PEX Gene Database; CC URL="https://databases.lovd.nl/shared/genes/PEX6"; 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; U56602; AAC50655.1; -; Genomic_DNA. DR EMBL; D83703; BAA12069.1; -; mRNA. DR EMBL; AF108098; AAF62564.1; -; Genomic_DNA. DR EMBL; AF108095; AAF62564.1; JOINED; Genomic_DNA. DR EMBL; AF108096; AAF62564.1; JOINED; Genomic_DNA. DR EMBL; AF108097; AAF62564.1; JOINED; Genomic_DNA. DR EMBL; AB051076; BAB83046.1; -; mRNA. DR EMBL; AB051077; BAB83047.1; -; mRNA. DR EMBL; AB051078; BAB83048.1; -; mRNA. DR EMBL; AK314237; BAG36906.1; -; mRNA. DR EMBL; AL158815; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471081; EAX04125.1; -; Genomic_DNA. DR EMBL; CH471081; EAX04128.1; -; Genomic_DNA. DR EMBL; CH471081; EAX04129.1; -; Genomic_DNA. DR EMBL; BC048331; AAH48331.1; -; mRNA. DR CCDS; CCDS4877.1; -. [Q13608-1] DR PIR; S71090; S71090. DR RefSeq; NP_000278.3; NM_000287.3. [Q13608-1] DR RefSeq; NP_001303242.1; NM_001316313.1. [Q13608-3] DR AlphaFoldDB; Q13608; -. DR SMR; Q13608; -. DR BioGRID; 111213; 126. DR CORUM; Q13608; -. DR IntAct; Q13608; 16. DR MINT; Q13608; -. DR STRING; 9606.ENSP00000303511; -. DR TCDB; 3.A.20.1.1; the peroxisomal protein importer (ppi) family. DR iPTMnet; Q13608; -. DR PhosphoSitePlus; Q13608; -. DR BioMuta; PEX6; -. DR DMDM; 12644408; -. DR EPD; Q13608; -. DR jPOST; Q13608; -. DR MassIVE; Q13608; -. DR PaxDb; Q13608; -. DR PeptideAtlas; Q13608; -. DR ProteomicsDB; 59595; -. [Q13608-1] DR ProteomicsDB; 75184; -. DR ABCD; Q13608; 1 sequenced antibody. DR Antibodypedia; 16146; 250 antibodies from 33 providers. DR DNASU; 5190; -. DR Ensembl; ENST00000244546.4; ENSP00000244546.4; ENSG00000124587.14. [Q13608-2] DR Ensembl; ENST00000304611.13; ENSP00000303511.8; ENSG00000124587.14. [Q13608-1] DR GeneID; 5190; -. DR KEGG; hsa:5190; -. DR MANE-Select; ENST00000304611.13; ENSP00000303511.8; NM_000287.4; NP_000278.3. DR UCSC; uc003otf.4; human. [Q13608-1] DR AGR; HGNC:8859; -. DR CTD; 5190; -. DR DisGeNET; 5190; -. DR GeneCards; PEX6; -. DR GeneReviews; PEX6; -. DR HGNC; HGNC:8859; PEX6. DR HPA; ENSG00000124587; Tissue enhanced (pancreas). DR MalaCards; PEX6; -. DR MIM; 601498; gene. DR MIM; 614862; phenotype. DR MIM; 614863; phenotype. DR MIM; 616617; phenotype. DR neXtProt; NX_Q13608; -. DR OpenTargets; ENSG00000124587; -. DR Orphanet; 95433; Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome. DR Orphanet; 3220; Deafness-enamel hypoplasia-nail defects syndrome. DR Orphanet; 772; Infantile Refsum disease. DR Orphanet; 44; Neonatal adrenoleukodystrophy. DR Orphanet; 912; Zellweger syndrome. DR PharmGKB; PA33201; -. DR VEuPathDB; HostDB:ENSG00000124587; -. DR eggNOG; KOG0736; Eukaryota. DR GeneTree; ENSGT00550000074953; -. DR HOGENOM; CLU_000688_0_8_1; -. DR InParanoid; Q13608; -. DR OMA; IPSVFWQ; -. DR OrthoDB; 7477at2759; -. DR PhylomeDB; Q13608; -. DR TreeFam; TF106428; -. DR BRENDA; 3.6.4.7; 2681. DR PathwayCommons; Q13608; -. DR Reactome; R-HSA-9033241; Peroxisomal protein import. DR SignaLink; Q13608; -. DR SIGNOR; Q13608; -. DR BioGRID-ORCS; 5190; 82 hits in 1166 CRISPR screens. DR ChiTaRS; PEX6; human. DR GeneWiki; PEX6; -. DR GenomeRNAi; 5190; -. DR Pharos; Q13608; Tbio. DR PRO; PR:Q13608; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q13608; protein. DR Bgee; ENSG00000124587; Expressed in right uterine tube and 142 other tissues. DR ExpressionAtlas; Q13608; baseline and differential. DR Genevisible; Q13608; HS. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB. DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB. DR GO; GO:0097733; C:photoreceptor cell cilium; IDA:UniProtKB. DR GO; GO:0001750; C:photoreceptor outer segment; IEA:UniProtKB-SubCell. DR GO; GO:0005524; F:ATP binding; IMP:UniProtKB. DR GO; GO:0016887; F:ATP hydrolysis activity; IMP:UniProtKB. DR GO; GO:0140318; F:protein transporter activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB. DR GO; GO:0140036; F:ubiquitin-dependent protein binding; IDA:UniProtKB. DR GO; GO:0007031; P:peroxisome organization; IMP:UniProtKB. DR GO; GO:0016558; P:protein import into peroxisome matrix; IBA:GO_Central. DR GO; GO:0016562; P:protein import into peroxisome matrix, receptor recycling; IDA:UniProtKB. DR GO; GO:0016561; P:protein import into peroxisome matrix, translocation; IMP:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0006625; P:protein targeting to peroxisome; IMP:UniProtKB. DR GO; GO:0043335; P:protein unfolding; IDA:UniProtKB. DR CDD; cd19527; RecA-like_PEX6_r2; 1. DR CDD; cd19481; RecA-like_protease; 1. DR Gene3D; 1.10.8.60; -; 2. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR InterPro; IPR003593; AAA+_ATPase. DR InterPro; IPR003959; ATPase_AAA_core. DR InterPro; IPR003960; ATPase_AAA_CS. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR047533; RecA-like_PEX6_r2. DR PANTHER; PTHR23077; AAA-FAMILY ATPASE; 1. DR PANTHER; PTHR23077:SF9; PEROXISOME ASSEMBLY FACTOR 2; 1. DR Pfam; PF00004; AAA; 2. DR SMART; SM00382; AAA; 2. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2. DR PROSITE; PS00674; AAA; 1. PE 1: Evidence at protein level; KW Alternative splicing; Amelogenesis imperfecta; ATP-binding; KW Cell projection; Cytoplasm; Deafness; Disease variant; Hydrolase; Membrane; KW Methylation; Nucleotide-binding; Peroxisome; Peroxisome biogenesis; KW Peroxisome biogenesis disorder; Reference proteome; Repeat; KW Zellweger syndrome. FT CHAIN 1..980 FT /note="Peroxisomal ATPase PEX6" FT /id="PRO_0000084607" FT BINDING 470..477 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255" FT BINDING 744..751 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255" FT MOD_RES 119 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT VAR_SEQ 207..294 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:11355018" FT /id="VSP_057137" FT VAR_SEQ 699..738 FT /note="IPSVSWHDVGGLQEVKKEILETIQLPLEHPELLSLGLRRS -> VETKSLEC FT LPGPGLQLHALSSLMNWTLWPQAGGEVEILEE (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11355018" FT /id="VSP_057138" FT VAR_SEQ 739..980 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11355018" FT /id="VSP_057139" FT VARIANT 79 FT /note="A -> P (in dbSNP:rs61752141)" FT /evidence="ECO:0000269|PubMed:19105186" FT /id="VAR_058381" FT VARIANT 92 FT /note="V -> G (in HMLR2; unknown pathological significance; FT dbSNP:rs886037780)" FT /evidence="ECO:0000269|PubMed:27302843" FT /id="VAR_077505" FT VARIANT 99 FT /note="R -> L (in HMLR2; unknown pathological significance; FT dbSNP:rs886037781)" FT /evidence="ECO:0000269|PubMed:27302843" FT /id="VAR_077506" FT VARIANT 218 FT /note="F -> L (in HMLR2; unknown pathological significance; FT dbSNP:rs886037779)" FT /evidence="ECO:0000269|PubMed:27302843" FT /id="VAR_077507" FT VARIANT 274 FT /note="P -> L (in HMLR2; results in severe functional FT decrease in peroxisome biogenesis; dbSNP:rs61753219)" FT /evidence="ECO:0000269|PubMed:19105186, FT ECO:0000269|PubMed:26387595" FT /id="VAR_058382" FT VARIANT 413 FT /note="G -> V (in PBD-CG4; disease phenotype includes FT hearing loss, visual impairment, enamel dysplasia FT microcephaly with deep white matter changes and FT developmental delay; dbSNP:rs1554127531)" FT /evidence="ECO:0000269|PubMed:26593283" FT /id="VAR_077508" FT VARIANT 534 FT /note="L -> P (in PBD-CG4; dbSNP:rs387906809)" FT /evidence="ECO:0000269|PubMed:21937992" FT /id="VAR_075872" FT VARIANT 572 FT /note="T -> I (in HMLR2; dbSNP:rs61753224)" FT /evidence="ECO:0000269|PubMed:27302843" FT /id="VAR_077509" FT VARIANT 601 FT /note="R -> Q (in HMLR2; unknown pathological significance; FT results in mild functional decrease in peroxisome FT biogenesis; dbSNP:rs34324426)" FT /evidence="ECO:0000269|PubMed:19105186, FT ECO:0000269|PubMed:26387595, ECO:0000269|PubMed:27302843" FT /id="VAR_058383" FT VARIANT 644 FT /note="R -> W (in HMLR2; results in mild functional FT decrease in peroxisome biogenesis; dbSNP:rs769896492)" FT /evidence="ECO:0000269|PubMed:26387595" FT /id="VAR_074110" FT VARIANT 809 FT /note="A -> V (in dbSNP:rs35830695)" FT /evidence="ECO:0000269|PubMed:19105186" FT /id="VAR_048114" FT VARIANT 812 FT /note="R -> Q (in PBD4A; dbSNP:rs61753229)" FT /evidence="ECO:0000269|PubMed:10408779" FT /id="VAR_007918" FT VARIANT 812 FT /note="R -> W (in PBD4A; atypical; dbSNP:rs61753228)" FT /evidence="ECO:0000269|PubMed:10408779" FT /id="VAR_007919" FT VARIANT 849 FT /note="N -> T (in PBD-CG4; dbSNP:rs267608244)" FT /evidence="ECO:0000269|PubMed:19105186" FT /id="VAR_058384" FT VARIANT 860 FT /note="R -> Q (in PBD-CG4; dbSNP:rs61753231)" FT /evidence="ECO:0000269|PubMed:19105186" FT /id="VAR_058385" FT VARIANT 860 FT /note="R -> W (in PBD-CG4; dbSNP:rs61753230)" FT /evidence="ECO:0000269|PubMed:19105186" FT /id="VAR_058386" FT VARIANT 882 FT /note="V -> I (in dbSNP:rs2274516)" FT /evidence="ECO:0000269|PubMed:19105186" FT /id="VAR_048115" FT VARIANT 905 FT /note="C -> F (in HMLR2; dbSNP:rs886037782)" FT /evidence="ECO:0000269|PubMed:27302843" FT /id="VAR_077510" FT VARIANT 924 FT /note="A -> S (in dbSNP:rs34551839)" FT /evidence="ECO:0000269|PubMed:19105186" FT /id="VAR_058387" FT VARIANT 939 FT /note="P -> Q (in dbSNP:rs1129187)" FT /evidence="ECO:0000269|PubMed:11355018, FT ECO:0000269|PubMed:19105186" FT /id="VAR_048116" FT MUTAGEN 476 FT /note="K->E: In A1 mutant; abolished ATP-binding; decreased FT interaction with PEX1 or PEX26." FT /evidence="ECO:0000269|PubMed:16854980, FT ECO:0000269|PubMed:21362118" FT MUTAGEN 532 FT /note="D->N: In B1 mutant; abolished ATP hydrolysis; does FT not affect interaction with PEX6 or PEX26." FT /evidence="ECO:0000269|PubMed:16854980, FT ECO:0000269|PubMed:21362118" FT MUTAGEN 750 FT /note="K->E: In A2 mutant; abolished ATP-binding; decreased FT interaction with PEX1 or PEX26." FT /evidence="ECO:0000269|PubMed:16854980, FT ECO:0000269|PubMed:21362118" FT MUTAGEN 803 FT /note="D->N: In B2 mutant; does not affect interaction with FT PEX6 or PEX26." FT /evidence="ECO:0000269|PubMed:16854980, FT ECO:0000269|PubMed:21362118" FT CONFLICT 77 FT /note="S -> N (in Ref. 1; AAC50655)" FT /evidence="ECO:0000305" SQ SEQUENCE 980 AA; 104061 MW; 0EC1C2A75CE0038F CRC64; MALAVLRVLE PFPTETPPLA VLLPPGGPWP AAELGLVLAL RPAGESPAGP ALLVAALEGP DAGTEEQGPG PPQLLVSRAL LRLLALGSGA WVRARAVRRP PALGWALLGT SLGPGLGPRV GPLLVRRGET LPVPGPRVLE TRPALQGLLG PGTRLAVTEL RGRARLCPES GDSSRPPPPP VVSSFAVSGT VRRLQGVLGG TGDSLGVSRS CLRGLGLFQG EWVWVAQARE SSNTSQPHLA RVQVLEPRWD LSDRLGPGSG PLGEPLADGL ALVPATLAFN LGCDPLEMGE LRIQRYLEGS IAPEDKGSCS LLPGPPFARE LHIEIVSSPH YSTNGNYDGV LYRHFQIPRV VQEGDVLCVP TIGQVEILEG SPEKLPRWRE MFFKVKKTVG EAPDGPASAY LADTTHTSLY MVGSTLSPVP WLPSEESTLW SSLSPPGLEA LVSELCAVLK PRLQPGGALL TGTSSVLLRG PPGCGKTTVV AAACSHLGLH LLKVPCSSLC AESSGAVETK LQAIFSRARR CRPAVLLLTA VDLLGRDRDG LGEDARVMAV LRHLLLNEDP LNSCPPLMVV ATTSRAQDLP ADVQTAFPHE LEVPALSEGQ RLSILRALTA HLPLGQEVNL AQLARRCAGF VVGDLYALLT HSSRAACTRI KNSGLAGGLT EEDEGELCAA GFPLLAEDFG QALEQLQTAH SQAVGAPKIP SVSWHDVGGL QEVKKEILET IQLPLEHPEL LSLGLRRSGL LLHGPPGTGK TLLAKAVATE CSLTFLSVKG PELINMYVGQ SEENVREVFA RARAAAPCII FFDELDSLAP SRGRSGDSGG VMDRVVSQLL AELDGLHSTQ DVFVIGATNR PDLLDPALLR PGRFDKLVFV GANEDRASQL RVLSAITRKF KLEPSVSLVN VLDCCPPQLT GADLYSLCSD AMTAALKRRV HDLEEGLEPG SSALMLTMED LLQAAARLQP SVSEQELLRY KRIQRKFAAC //