O60220 (TIM8A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitochondrial import inner membrane translocase subunit Tim8 A

Alternative name(s):
Deafness dystonia protein 1
X-linked deafness dystonia protein

Gene names

Name:	TIMM8A
Synonyms:	DDP, DDP1, TIM8A

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	97 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins. Probably necessary for normal neurologic development. Ref.6 Ref.7 Ref.8 Ref.9
Subunit structure	Heterohexamer; composed of 3 copies of TIMM8A and 3 copies of TIMM13, named soluble 70 kDa complex. Associates with the TIM22 complex, whose core is composed of TIMM22.
Subcellular location	Mitochondrion inner membrane; Peripheral membrane protein; Intermembrane side Ref.8.
Tissue specificity	Highly expressed in fetal and adult brain, followed by fetal lung, liver and kidney. Also expressed in heart, placenta, lung, liver, kidney, pancreas, skeletal muscle and heart.
Domain	The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM8A from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane By similarity.
Involvement in disease	Defects in TIMM8A are the cause of Mohr-Tranebjaerg syndrome (MTS) [MIM:304700]; also known as dystonia-deafness syndrome (DDS) or X-linked progressive deafness type 1 (DFN-1). It is a recessive neurodegenerative syndrome characterized by postlingual progressive sensorineural deafness as the first presenting symptom in early childhood, followed by progressive dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. Ref.13 Ref.14 Ref.15 Defects in TIMM8A are the cause of Jensen syndrome (JENSS) [MIM:311150]; also known as opticoacoustic nerve atrophy with dementia. This X-linked disease is characterized by deafness, blindness and muscle weakness.
Sequence similarities	Belongs to the small Tim family.

Ontologies

Keywords
Biological process	Protein transport Translocation Transport
Cellular component	Membrane Mitochondrion Mitochondrion inner membrane
Disease	Deafness Disease mutation
Ligand	Metal-binding Zinc
Molecular function	Chaperone
PTM	Acetylation Disulfide bond Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	chaperone-mediated protein transport Traceable author statement. Source: BHF-UCL nervous system development Traceable author statement. Source: ProtInc protein import into mitochondrial inner membrane Inferred from electronic annotation. Source: InterPro
Cellular component	mitochondrial inner membrane Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrial intermembrane space protein transporter complex Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 97	97	Mitochondrial import inner membrane translocase subunit Tim8 A		PRO_0000193584
Regions
	Motif	43 – 66	24	Twin CX3C motif
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine Ref.11
	Modified residue	94	1	Phosphoserine Ref.10
	Disulfide bond	43 ↔ 66		By similarity
	Disulfide bond	47 ↔ 62		By similarity
Natural variations
	Natural variant	66	1	C → W in MTS; disrupts the assembly of the heterohexamer with TIMM13. Ref.13 Ref.14 Ref.15		VAR_010237
Experimental info
	Sequence conflict	62	1	C → R in AAH70284. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	O60220 [UniParc]. Last modified August 1, 1998. Version 1. Checksum: CB72822290F20AB0	FASTA	97	10,998
	10 20 30 40 50 60 MDSSSSSSAA GLGAVDPQLQ HFIEVETQKQ RFQQLVHQMT ELCWEKCMDK PGPKLDSRAE 70 80 90 ACFVNCVERF IDTSQFILNR LEQTQKSKPV FSESLSD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness." Jin H., May M., Tranebjaerg L., Kendall E., Fontan G., Jackson J., Subramony S.H., Arena F., Lubs H., Smith S., Stevenson R., Schwartz C., Vetrie D. Nat. Genet. 14:177-180(1996) [PubMed: 8841189] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Tongue.
[3]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed: 15772651] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain, Kidney and Urinary bladder.
[6]	"Human deafness dystonia syndrome is a mitochondrial disease." Koehler C.M., Leuenberger D., Merchant S., Renold A., Junne T., Schatz G. Proc. Natl. Acad. Sci. U.S.A. 96:2141-2146(1999) [PubMed: 10051608] [Abstract] Cited for: PROBABLE FUNCTION.
[7]	"Mitochondria and dystonia: the movement disorder connection?" Wallace D.C., Murdock D.G. Proc. Natl. Acad. Sci. U.S.A. 96:1817-1819(1999) [PubMed: 10051550] [Abstract] Cited for: PROBABLE FUNCTION.
[8]	"Role of the deafness dystonia peptide 1 (DDP1) in import of human Tim23 into the inner membrane of mitochondria." Rothbauer U., Hofmann S., Muehlenbein N., Paschen S.A., Gerbitz K.-D., Neupert W., Brunner M., Bauer M.F. J. Biol. Chem. 276:37327-37334(2001) [PubMed: 11489896] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, ZINC-BINDING, INTERACTION WITH TIMM13.
[9]	"The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex." Roesch K., Hynds P.J., Varga R., Tranebjaerg L., Koehler C.M. Hum. Mol. Genet. 13:2101-2111(2004) [PubMed: 15254020] [Abstract] Cited for: FUNCTION.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-94, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[12]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome." Tranebjaerg L., Hamel B.C.J., Gabreels F.J.M., Renier W.O., Van Ghelue M. Eur. J. Hum. Genet. 8:464-467(2000) [PubMed: 10878669] [Abstract] Cited for: VARIANT MTS TRP-66.
[14]	"Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex." Roesch K., Curran S.P., Tranebjaerg L., Koehler C.M. Hum. Mol. Genet. 11:477-486(2002) [PubMed: 11875042] [Abstract] Cited for: VARIANT MTS TRP-66.
[15]	"The C66W mutation in the deafness dystonia peptide 1 (DDP1) affects the formation of functional DDP1.TIM13 complexes in the mitochondrial intermembrane space." Hofmann S., Rothbauer U., Muehlenbein N., Neupert W., Gerbitz K.-D., Brunner M., Bauer M.F. J. Biol. Chem. 277:23287-23293(2002) [PubMed: 11956200] [Abstract] Cited for: VARIANT MTS TRP-66.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	U66035 mRNA. Translation: AAC15946.1. AK312117 mRNA. Translation: BAG35053.1. AL035422 Genomic DNA. Translation: CAB55875.1. CH471115 Genomic DNA. Translation: EAX02854.1. BC006994 mRNA. Translation: AAH06994.1. BC015093 mRNA. Translation: AAH15093.1. BC070284 mRNA. Translation: AAH70284.1.
IPI	IPI00028376.
RefSeq	NP_004076.1. NM_004085.3.
UniGene	Hs.447877.
3D structure databases
ProteinModelPortal	O60220.
SMR	O60220. Positions 28-84.
ModBase	Search...
Protein-protein interaction databases
IntAct	O60220. 2 interactions.
MINT	MINT-2999881.
STRING	O60220.
PTM databases
PhosphoSite	O60220.
Proteomic databases
PeptideAtlas	O60220.
PRIDE	O60220.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000372902; ENSP00000361993; ENSG00000126953.
GeneID	1678.
KEGG	hsa:1678.
UCSC	uc004ehd.1. human.
Organism-specific databases
CTD	1678.
GeneCards	GC0XM100600.
H-InvDB	HIX0016925.
HGNC	HGNC:11817. TIMM8A.
HPA	HPA003628.
MIM	300356. gene. 304700. phenotype. 311150. phenotype.
neXtProt	NX_O60220.
Orphanet	3213. Deafness - opticoacoustic nerve atrophy - dementia. 52368. Mohr-Tranebjaerg syndrome.
PharmGKB	PA36523.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG20474.
GeneTree	ENSGT00390000016102.
HOGENOM	HBG603145.
HOVERGEN	HBG060492.
InParanoid	O60220.
OMA	DSRAETC.
OrthoDB	EOG408N9N.
PhylomeDB	O60220.
Gene expression databases
ArrayExpress	O60220.
Bgee	O60220.
CleanEx	HS_TIMM8A.
Genevestigator	O60220.
GermOnline	ENSG00000126953. Homo sapiens.
Family and domain databases
InterPro	IPR004217. Tim8/9/10/13_Znf-like. [Graphical view]
Gene3D	G3DSA:1.10.287.810. G3DSA:1.10.287.810. 1 hit.
Pfam	PF02953. zf-Tim10_DDP. 1 hit. [Graphical view]
SUPFAM	SSF144122. SSF144122. 1 hit.
ProtoNet	Search...
Other
NextBio	6906.
SOURCE	Search...

Entry information

Entry name

TIM8A_HUMAN

Accession

Primary (citable) accession number: O60220
Secondary accession number(s): B2R5A6, Q6IRW6

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	August 1, 1998
Last modified:	January 25, 2012
This is version 107 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.