Q9Y4W6 (AFG32_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
AFG3-like protein 2
EC=3.4.24.-

Alternative name(s):
Paraplegin-like protein

Gene names

Name:

AFG3L2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	797 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	ATP-dependent protease which is essential for axonal development By similarity.
Cofactor	Binds 1 zinc ion per subunit Potential.
Subunit structure	Homooligomer. Interacts with SPG7; the interaction is required for the efficient assembly of mitochondrial complex I. Ref.3 Ref.4
Subcellular location	Mitochondrion membrane; Multi-pass membrane protein Ref.1.
Tissue specificity	Ubiquitous. Highly expressed in the cerebellar Purkinje cells. Ref.9
Involvement in disease	Spinocerebellar ataxia 28 (SCA28) [MIM:610246]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA28 is an autosomal dominant cerebellar ataxia (ADCA) with a slow progressive course and no evidence of sensory involvement or cognitive impairment. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7 Ref.8 Ref.9 Spastic ataxia autosomal recessive 5 (SPAX5) [MIM:614487]: A neurodegenerative disorder characterized by early onset spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10
Sequence similarities	In the N-terminal section; belongs to the AAA ATPase family. In the C-terminal section; belongs to the peptidase M41 family.

Ontologies

Keywords
Cellular component	Membrane Mitochondrion
Disease	Disease mutation Neurodegeneration Spinocerebellar ataxia
Domain	Transmembrane Transmembrane helix
Ligand	ATP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	axonogenesis Inferred from electronic annotation. Source: Compara cell death Inferred from electronic annotation. Source: UniProtKB-KW cristae formation Inferred from electronic annotation. Source: Compara mitochondrial fusion Inferred from electronic annotation. Source: Compara mitochondrial protein processing Inferred from electronic annotation. Source: Compara myelination Inferred from electronic annotation. Source: Compara nerve development Inferred from electronic annotation. Source: Compara neuromuscular junction development Inferred from electronic annotation. Source: Compara protein catabolic process Inferred from electronic annotation. Source: InterPro proteolysis Inferred from electronic annotation. Source: UniProtKB-KW regulation of multicellular organism growth Inferred from electronic annotation. Source: Compara righting reflex Inferred from electronic annotation. Source: Compara
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial inner membrane Inferred from electronic annotation. Source: Compara mitochondrion Inferred from direct assay. Source: HPA
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro nucleoside-triphosphatase activity Inferred from electronic annotation. Source: InterPro unfolded protein binding Traceable author statement Ref.1. Source: ProtInc zinc ion binding 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 – 797

797

AFG3-like protein 2

PRO_0000084673

Regions

Transmembrane

143 – 163

21

Helical; Potential

Transmembrane

251 – 271

21

Helical; Potential

Nucleotide binding

348 – 355

8

ATP Potential

Sites

Active site

575

1

By similarity

Metal binding

574

1

Zinc; catalytic By similarity

Metal binding

578

1

Zinc; catalytic By similarity

Metal binding

649

1

Zinc; catalytic By similarity

Amino acid modifications

Modified residue

308

1

N6-acetyllysine By similarity

Modified residue

543

1

N6-acetyllysine By similarity

Natural variations

Natural variant

432

1

N → T in SCA28. Ref.9

VAR_063544

Natural variant

616

1

Y → C in SPAX5; hypomorphic mutation; results in impaired oligomerization with itself and SPG7; retains ATPase and proteolytic activities. Ref.10

VAR_067330

Natural variant

654

1

T → I in SCA28. Ref.8

VAR_064402

Natural variant

666

1

M → R in SCA28. Ref.8

VAR_064403

Natural variant

666

1

M → T in SCA28. Ref.8

VAR_064404

Natural variant

666

1

M → V in SCA28. Ref.8

VAR_064405

Natural variant

671

1

G → E in SCA28. Ref.8

VAR_064406

Natural variant

671

1

G → R in SCA28. Ref.8

VAR_064407

Natural variant

691

1

E → K in SCA28. Ref.9

VAR_063545

Natural variant

694

1

A → E in SCA28. Ref.9

VAR_063546

Natural variant

700

1

E → K in SCA28. Ref.7

VAR_064408

Natural variant

702

1

R → Q in SCA28. Ref.9

VAR_063547

Experimental info

Sequence conflict

74

1

E → G in CAB48398. Ref.1

Sequence conflict

633

1

V → A in CAB48398. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

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.

.

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797

Helix Strand Turn

Details...

Beta strand

165 – 169

5

Helix

172 – 178

7

Helix

180 – 182

3

Beta strand

185 – 191

7

Turn

192 – 194

3

Beta strand

195 – 200

6

Turn

202 – 204

3

Beta strand

212 – 215

4

Helix

219 – 232

14

Turn

237 – 239

3

Beta strand

243 – 245

3

Sequences

	Sequence		Length	Mass (Da)
	Q9Y4W6 [UniParc]. Last modified February 20, 2007. Version 2. Checksum: EACBB7C5F2EE5E08	FASTA	797	88,584
	10 20 30 40 50 60 MAHRCLRLWG RGGCWPRGLQ QLLVPGGVGP GEQPCLRTLY RFVTTQARAS RNSLLTDIIA 70 80 90 100 110 120 AYQRFCSRPP KGFEKYFPNG KNGKKASEPK EVMGEKKESK PAATTRSSGG GGGGGGKRGG 130 140 150 160 170 180 KKDDSHWWSR FQKGDIPWDD KDFRMFFLWT ALFWGGVMFY LLLKRSGREI TWKDFVNNYL 190 200 210 220 230 240 SKGVVDRLEV VNKRFVRVTF TPGKTPVDGQ YVWFNIGSVD TFERNLETLQ QELGIEGENR 250 260 270 280 290 300 VPVVYIAESD GSFLLSMLPT VLIIAFLLYT IRRGPAGIGR TGRGMGGLFS VGETTAKVLK 310 320 330 340 350 360 DEIDVKFKDV AGCEEAKLEI MEFVNFLKNP KQYQDLGAKI PKGAILTGPP GTGKTLLAKA 370 380 390 400 410 420 TAGEANVPFI TVSGSEFLEM FVGVGPARVR DLFALARKNA PCILFIDEID AVGRKRGRGN 430 440 450 460 470 480 FGGQSEQENT LNQLLVEMDG FNTTTNVVIL AGTNRPDILD PALLRPGRFD RQIFIGPPDI 490 500 510 520 530 540 KGRASIFKVH LRPLKLDSTL EKDKLARKLA SLTPGFSGAD VANVCNEAAL IAARHLSDSI 550 560 570 580 590 600 NQKHFEQAIE RVIGGLEKKT QVLQPEEKKT VAYHEAGHAV AGWYLEHADP LLKVSIIPRG 610 620 630 640 650 660 KGLGYAQYLP KEQYLYTKEQ LLDRMCMTLG GRVSEEIFFG RITTGAQDDL RKVTQSAYAQ 670 680 690 700 710 720 IVQFGMNEKV GQISFDLPRQ GDMVLEKPYS EATARLIDDE VRILINDAYK RTVALLTEKK 730 740 750 760 770 780 ADVEKVALLL LEKEVLDKND MVELLGPRPF AEKSTYEEFV EGTGSLDEDT SLPEGLKDWN 790 KEREKEKEEP PGEKVAN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification and characterization of AFG3L2, a novel paraplegin-related gene." Banfi S., Bassi M.T., Andolfi G., Marchitiello A., Zanotta S., Ballabio A., Casari G., Franco B. Genomics 59:51-58(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION.
[2]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Eye.
[3]	"Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia." Atorino L., Silvestri L., Koppen M., Cassina L., Ballabio A., Marconi R., Langer T., Casari G. J. Cell Biol. 163:777-787(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SPG7.
[4]	"Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia." Koppen M., Metodiev M.D., Casari G., Rugarli E.I., Langer T. Mol. Cell. Biol. 27:758-767(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT.
[5]	"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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[6]	"Northeast structural genomics consortium target HR6741A." Northeast structural genomics consortium (NESG) Submitted (MAR-2012) to the PDB data bank Cited for: STRUCTURE BY NMR OF 164-251.
[7]	"Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation." Edener U., Wollner J., Hehr U., Kohl Z., Schilling S., Kreuz F., Bauer P., Bernard V., Gillessen-Kaesbach G., Zuhlke C. Eur. J. Hum. Genet. 18:965-968(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SCA28 LYS-700.
[8]	"Missense mutations in the AFG3L2 proteolytic domain account for approximately 1.5% of European autosomal dominant cerebellar ataxias." Cagnoli C., Stevanin G., Brussino A., Barberis M., Mancini C., Margolis R.L., Holmes S.E., Nobili M., Forlani S., Padovan S., Pappi P., Zaros C., Leber I., Ribai P., Pugliese L., Assalto C., Brice A., Migone N., Durr A., Brusco A. Hum. Mutat. 31:1117-1124(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS SCA28 ILE-654; VAL-666; ARG-666; THR-666; ARG-671 AND GLU-671.
[9]	"Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28." Di Bella D., Lazzaro F., Brusco A., Plumari M., Battaglia G., Pastore A., Finardi A., Cagnoli C., Tempia F., Frontali M., Veneziano L., Sacco T., Boda E., Brussino A., Bonn F., Castellotti B., Baratta S., Mariotti C. , Gellera C., Fracasso V., Magri S., Langer T., Plevani P., Di Donato S., Muzi-Falconi M., Taroni F. Nat. Genet. 42:313-321(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS SCA28 THR-432; LYS-691; GLU-694 AND GLN-702, TISSUE SPECIFICITY.
[10]	"Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases." Pierson T.M., Adams D., Bonn F., Martinelli P., Cherukuri P.F., Teer J.K., Hansen N.F., Cruz P., Mullikin J.C., Blakesley R.W., Golas G., Kwan J., Sandler A., Fuentes Fajardo K., Markello T., Tifft C., Blackstone C., Rugarli E.I. , Langer T., Gahl W.A., Toro C. PLoS Genet. 7:E1002325-E1002325(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SPAX5 CYS-616, CHARACTERIZATION OF VARIANT SPAX5 CYS-616.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Y18314 mRNA. Translation: CAB48398.1.
BC065016 mRNA. Translation: AAH65016.1.

IPI

IPI00001091.

RefSeq

NP_006787.2. NM_006796.2.

UniGene

Hs.726355.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2LNA	NMR	-	A	164-251	[»]

ProteinModelPortal

Q9Y4W6.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9Y4W6. 9 interactions.

MINT

MINT-1161944.

STRING

9606.ENSP00000269143.

Protein family/group databases

MEROPS

M41.007.

PTM databases

PhosphoSite

Q9Y4W6.

Polymorphism databases

DMDM

126302516.

Proteomic databases

PaxDb

Q9Y4W6.

PeptideAtlas

Q9Y4W6.

PRIDE

Q9Y4W6.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000269143; ENSP00000269143; ENSG00000141385.

GeneID

10939.

KEGG

hsa:10939.

UCSC

uc002kqz.2. human.

Organism-specific databases

CTD

10939.

GeneCards

GC18M012328.

H-InvDB

HIX0027367.

HGNC

HGNC:315. AFG3L2.

HPA

HPA004479.
HPA004480.

MIM

604581. gene.
610246. phenotype.
614487. phenotype.

neXtProt

NX_Q9Y4W6.

Orphanet

313772. Early-onset spastic ataxia-neuropathy syndrome.
101109. Spinocerebellar ataxia type 28.

PharmGKB

PA24612.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0465.

HOVERGEN

HBG050184.

InParanoid

Q9Y4W6.

KO

K08956.

OrthoDB

EOG4SBDXC.

PhylomeDB

Q9Y4W6.

Gene expression databases

ArrayExpress

Q9Y4W6.

Bgee

Q9Y4W6.

CleanEx

HS_AFG3L2.

Genevestigator

Q9Y4W6.

GermOnline

ENSG00000141385. Homo sapiens.

Family and domain databases

InterPro

IPR003593. AAA+_ATPase.
IPR003959. ATPase_AAA_core.
IPR003960. ATPase_AAA_CS.
IPR005936. FtsH.
IPR027417. P-loop_NTPase.
IPR011546. Pept_M41_FtsH_extracell.
IPR000642. Peptidase_M41.
[Graphical view]

Pfam

PF00004. AAA. 1 hit.
PF06480. FtsH_ext. 1 hit.
PF01434. Peptidase_M41. 1 hit.
[Graphical view]

SMART

SM00382. AAA. 1 hit.
[Graphical view]

SUPFAM

SSF52540. SSF52540. 1 hit.

TIGRFAMs

TIGR01241. FtsH_fam. 1 hit.

PROSITE

PS00674. AAA. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00171. Adenosine triphosphate.

GenomeRNAi

10939.

NextBio

41551.

SOURCE

Search...

Entry information

Entry name

AFG32_HUMAN

Accession

Primary (citable) accession number: Q9Y4W6
Secondary accession number(s): Q6P1L0

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	February 20, 2007
Last modified:	May 29, 2013
This is version 128 of the entry and version 2 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.