Q9UQ90 (SPG7_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Paraplegin
EC=3.4.24.-

Alternative name(s):
Spastic paraplegia 7 protein

Gene names

Name:	SPG7
Synonyms:	CAR, CMAR, PGN

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	795 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Putative ATP-dependent zinc metalloprotease.
Subunit structure	Interacts with AFG3L2; the interaction is required for the efficient assembly of mitochondrial complex I. Ref.4
Subcellular location	Mitochondrion membrane; Multi-pass membrane protein Ref.1.
Tissue specificity	Ubiquitous.
Involvement in disease	Spastic paraplegia 7, autosomal recessive (SPG7) [MIM:607259]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG7 is a complex form. Additional clinical features are cerebellar syndrome, supranuclear palsy, and cognitive impairment, particularly disturbance of attention and executive functions. Note: The disease is caused by mutations affecting the gene represented in this entry. Defects in SPG7 may cause autosomal recessive osteogenesis imperfecta (OI). Osteogenesis imperfecta defines a group of connective tissue disorders characterized by bone fragility and low bone mass. Clinical features of SPG7-related osteogenesis imperfecta include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing and white sclera.
Sequence similarities	In the N-terminal section; belongs to the AAA ATPase family. In the C-terminal section; belongs to the peptidase M41 family.
Caution	A CDS in the 3'-UTR of SPG7 mRNA had been erroneously identified as a cell matrix adhesion regulator and originally thought to be encoded by the CMAR gene. There is no experimental evidence for the production of endogenous CMAR protein.
Sequence caution	The sequence AAH35929.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened. The sequence BC007692 differs from that shown. Reason: Erroneous termination at position 428. Translated as Glu.

Ontologies

Keywords
Cellular component	Membrane Mitochondrion
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Hereditary spastic paraplegia Neurodegeneration Osteogenesis imperfecta
Domain	Transmembrane Transmembrane helix
Ligand	ATP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Nitration
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	anterograde axon cargo transport Inferred from electronic annotation. Source: Compara cell death Inferred from electronic annotation. Source: UniProtKB-KW mitochondrion organization Inferred from electronic annotation. Source: Compara nervous system development Traceable author statement Ref.1. Source: ProtInc protein catabolic process Inferred from electronic annotation. Source: InterPro proteolysis Traceable author statement Ref.1. Source: ProtInc
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial membrane Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrion Traceable author statement Ref.1. Source: ProtInc
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW metalloendopeptidase activity Inferred from direct assay PubMed 11549317. Source: MGI 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...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9UQ90-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9UQ90-2)

The sequence of this isoform differs from the canonical sequence as follows:
     443-489: MGTTDHVIVL...PTLQERREIF → ASLDQLPSQG...HSLCWGCLLH
     490-795: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 795

795

Paraplegin

PRO_0000084675

Regions

Topological domain

1 – 144

144

Mitochondrial matrix Potential

Transmembrane

145 – 165

21

Helical; Potential

Topological domain

166 – 248

83

Mitochondrial intermembrane Potential

Transmembrane

249 – 269

21

Helical; Potential

Topological domain

270 – 795

526

Mitochondrial matrix Potential

Nucleotide binding

349 – 357

9

ATP

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

650

1

Zinc; catalytic By similarity

Binding site

173

1

ATP; via amide nitrogen and carbonyl oxygen

Binding site

492

1

ATP

Amino acid modifications

Modified residue

505

1

Nitrated tyrosine By similarity

Natural variations

Alternative sequence

443 – 489

47

MGTTD…RREIF → ASLDQLPSQGTMRKLRGKTP ACSCLTEPTGSRRAMEGHSL CWGCLLH in isoform 2.

VSP_009192

Alternative sequence

490 – 795

306

Missing in isoform 2.

VSP_009193

Natural variant

2

1

A → T. Ref.7

VAR_063603

Natural variant

82

1

Missing Might be implicated in the hereditary spastic paraplegia phenotype. Ref.7

VAR_063604

Natural variant

284

1

F → P Requires 2 nucleotide substitutions; might be implicated in the hereditary spastic paraplegia phenotype. Ref.7

VAR_063605

Natural variant

294

1

R → H. Ref.7

VAR_063606

Natural variant

349

1

G → S in SPG7; function impaired. Ref.9

VAR_063607

Natural variant

486

1

R → Q. Ref.7

VAR_063608

Natural variant

503

1

T → A Neutral polymorphism. Ref.7 Ref.9
Corresponds to variant rs2292954 [ dbSNP | Ensembl ].

VAR_017433

Natural variant

510

1

A → V in SPG7; function impaired. Ref.7 Ref.9

VAR_063609

Natural variant

545

1

F → L. Ref.7

VAR_063610

Natural variant

581

1

Missing in SPG7. Ref.7

VAR_063611

Natural variant

583

1

W → C in SPG7; function impaired. Ref.9

VAR_063612

Natural variant

603

1

A → T. Ref.7

VAR_063613

Natural variant

623

1

F → C.
Corresponds to variant rs17783943 [ dbSNP | Ensembl ].

VAR_048117

Natural variant

635

1

S → L Might be implicated in the hereditary spastic paraplegia phenotype. Ref.7

VAR_063614

Natural variant

645

1

S → T. Ref.7
Corresponds to variant rs2099104 [ dbSNP | Ensembl ].

VAR_059086

Natural variant

650

1

D → H Might be implicated in the hereditary spastic paraplegia phenotype. Ref.7

VAR_063615

Natural variant

688

1

R → Q Neutral polymorphism. Ref.7 Ref.9
Corresponds to variant rs12960 [ dbSNP | Ensembl ].

VAR_017434

Natural variant

692

1

S → T in SPG7. Ref.8

VAR_045898

Natural variant

730

1

N → D. Ref.7
Corresponds to variant rs35749032 [ dbSNP | Ensembl ].

VAR_048118

Experimental info

Sequence conflict

12

1

R → G in AAD28099. Ref.2

Sequence conflict

376

1

P → A in AAH36104. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

795

Helix Strand Turn

Details...

Helix

315 – 329

15

Beta strand

344 – 349

6

Helix

355 – 366

12

Beta strand

370 – 374

5

Turn

375 – 378

4

Beta strand

379 – 382

4

Helix

385 – 399

15

Beta strand

402 – 408

7

Helix

431 – 441

11

Beta strand

449 – 456

8

Helix

458 – 462

5

Helix

464 – 466

3

Beta strand

473 – 476

4

Helix

482 – 495

14

Helix

502 – 511

10

Helix

518 – 529

12

Helix

545 – 557

13

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 17, 2006. Version 2. Checksum: 453D4BF8553A0632	FASTA	795	88,235
	10 20 30 40 50 60 MAVLLLLLRA LRRGPGPGPR PLWGPGPAWS PGFPARPGRG RPYMASRPPG DLAEAGGRAL 70 80 90 100 110 120 QSLQLRLLTP TFEGINGLLL KQHLVQNPVR LWQLLGGTFY FNTSRLKQKN KEKDKSKGKA 130 140 150 160 170 180 PEEDEEERRR RERDDQMYRE RLRTLLVIAV VMSLLNALST SGGSISWNDF VHEMLAKGEV 190 200 210 220 230 240 QRVQVVPESD VVEVYLHPGA VVFGRPRLAL MYRMQVANID KFEEKLRAAE DELNIEAKDR 250 260 270 280 290 300 IPVSYKRTGF FGNALYSVGM TAVGLAILWY VFRLAGMTGR EGGFSAFNQL KMARFTIVDG 310 320 330 340 350 360 KMGKGVSFKD VAGMHEAKLE VREFVDYLKS PERFLQLGAK VPKGALLLGP PGCGKTLLAK 370 380 390 400 410 420 AVATEAQVPF LAMAGPEFVE VIGGLGAARV RSLFKEARAR APCIVYIDEI DAVGKKRSTT 430 440 450 460 470 480 MSGFSNTEEE QTLNQLLVEM DGMGTTDHVI VLASTNRADI LDGALMRPGR LDRHVFIDLP 490 500 510 520 530 540 TLQERREIFE QHLKSLKLTQ SSTFYSQRLA ELTPGFSGAD IANICNEAAL HAAREGHTSV 550 560 570 580 590 600 HTLNFEYAVE RVLAGTAKKS KILSKEEQKV VAFHESGHAL VGWMLEHTEA VMKVSITPRT 610 620 630 640 650 660 NAALGFAQML PRDQHLFTKE QLFERMCMAL GGRASEALSF NEVTSGAQDD LRKVTRIAYS 670 680 690 700 710 720 MVKQFGMAPG IGPISFPEAQ EGLMGIGRRP FSQGLQQMMD HEARLLVAKA YRHTEKVLQD 730 740 750 760 770 780 NLDKLQALAN ALLEKEVINY EDIEALIGPP PHGPKKMIAP QRWIDAQREK QDLGEEETEE 790 TQQPPLGGEE PTWPK
	Isoform 2 [UniParc]. Checksum: 32CDE9E69A1918F9	FASTA	489	53,940
	10 20 30 40 50 60 MAVLLLLLRA LRRGPGPGPR PLWGPGPAWS PGFPARPGRG RPYMASRPPG DLAEAGGRAL 70 80 90 100 110 120 QSLQLRLLTP TFEGINGLLL KQHLVQNPVR LWQLLGGTFY FNTSRLKQKN KEKDKSKGKA 130 140 150 160 170 180 PEEDEEERRR RERDDQMYRE RLRTLLVIAV VMSLLNALST SGGSISWNDF VHEMLAKGEV 190 200 210 220 230 240 QRVQVVPESD VVEVYLHPGA VVFGRPRLAL MYRMQVANID KFEEKLRAAE DELNIEAKDR 250 260 270 280 290 300 IPVSYKRTGF FGNALYSVGM TAVGLAILWY VFRLAGMTGR EGGFSAFNQL KMARFTIVDG 310 320 330 340 350 360 KMGKGVSFKD VAGMHEAKLE VREFVDYLKS PERFLQLGAK VPKGALLLGP PGCGKTLLAK 370 380 390 400 410 420 AVATEAQVPF LAMAGPEFVE VIGGLGAARV RSLFKEARAR APCIVYIDEI DAVGKKRSTT 430 440 450 460 470 480 MSGFSNTEEE QTLNQLLVEM DGASLDQLPS QGTMRKLRGK TPACSCLTEP TGSRRAMEGH SLCWGCLLH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease." Casari G., De Fusco M., Ciarmatori S., Zeviani M., Mora M., Fernandez P., De Michele G., Filla A., Cocozza S., Marconi R., Duerr A., Fontaine B., Ballabio A. Cell 93:973-983(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, INVOLVEMENT IN SPG7.
[2]	"Genomic structure and expression analysis of the spastic paraplegia gene, SPG7." Settasatian C., Whitmore S.A., Crawford J., Bilton R.L., Cleton-Jansen A.-M., Sutherland G.R., Callen D.F. Hum. Genet. 105:139-144(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[3]	"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] (ISOFORMS 1 AND 2). Tissue: Duodenum and Placenta.
[4]	"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 AFG3L2.
[5]	"Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta." Lapunzina P., Aglan M., Temtamy S., Caparros-Martin J.A., Valencia M., Leton R., Martinez-Glez V., Elhossini R., Amr K., Vilaboa N., Ruiz-Perez V.L. Am. J. Hum. Genet. 87:110-114(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN OSTEOGENESIS IMPERFECTA.
[6]	"Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7." Karlberg T., van den Berg S., Hammarstrom M., Sagemark J., Johansson I., Holmberg-Schiavone L., Schuler H. PLoS ONE 4:E6975-E6975(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.22 ANGSTROMS) OF 305-565 IN COMPLEX WITH ADP.
[7]	"Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia." Elleuch N., Depienne C., Benomar A., Hernandez A.M., Ferrer X., Fontaine B., Grid D., Tallaksen C.M.E., Zemmouri R., Stevanin G., Durr A., Brice A. Neurology 66:654-659(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS SPG7 VAL-510 AND VAL-581 DEL, VARIANTS THR-2; GLN-82 DEL; PRO-284; HIS-294; GLN-486 ALA-503; LEU-545; THR-603; LEU-635; THR-645; HIS-650; GLN-688 AND ASP-730.
[8]	"A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation." Warnecke T., Duning T., Schwan A., Lohmann H., Epplen J.T., Young P. Neurology 69:368-375(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SPG7 THR-692.
[9]	"Functional evaluation of paraplegin mutations by a yeast complementation assay." Bonn F., Pantakani K., Shoukier M., Langer T., Mannan A.U. Hum. Mutat. 31:617-621(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS SPG7 SER-349; VAL-510 AND CYS-583, VARIANTS ALA-503 AND GLN-688, CHARACTERIZATION OF VARIANTS SPG7 SER-349; VAL-510 AND CYS-583, CHARACTERIZATION OF VARIANTS ALA-503 AND GLN-688.
+	Additional computationally mapped references.

Web resources

GeneReviews

Osteogenesis imperfecta variant database

Paraplegin (SPG7)

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Y16610 mRNA. Translation: CAA76314.1.
AF080525 , AF080511, AF080512, AF080513, AF080514, AF080515, AF080516, AF080517, AF080518, AF080519, AF080520, AF080521, AF080522, AF080523, AF080524 Genomic DNA. Translation: AAD28099.1.
BC007692 mRNA. No translation available.
BC035929 mRNA. Translation: AAH35929.1. Different initiation.
BC036104 mRNA. Translation: AAH36104.1.
BC110530 mRNA. No translation available.
BC110531 mRNA. No translation available.

IPI

IPI00299010.
IPI00398508.

RefSeq

NP_003110.1. NM_003119.2.
NP_955399.1. NM_199367.1.

UniGene

Hs.185597.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2QZ4	X-ray	2.22	A	305-565	[»]

ProteinModelPortal

Q9UQ90.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9UQ90. 8 interactions.

MINT

MINT-3083741.

STRING

9606.ENSP00000268704.

Protein family/group databases

MEROPS

M41.006.

PTM databases

PhosphoSite

Q9UQ90.

Polymorphism databases

DMDM

116242796.

Proteomic databases

PaxDb

Q9UQ90.

PRIDE

Q9UQ90.

Protocols and materials databases

DNASU

6687.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000268704; ENSP00000268704; ENSG00000197912.
ENST00000341316; ENSP00000341157; ENSG00000197912.

GeneID

6687.

KEGG

hsa:6687.

UCSC

uc002fni.3. human.
uc002fnj.3. human.

Organism-specific databases

CTD

6687.

GeneCards

GC16P089574.

HGNC

HGNC:11237. SPG7.

MIM

602783. gene.
607259. phenotype.

neXtProt

NX_Q9UQ90.

Orphanet

250932. Autosomal dominant optic atrophy and peripheral neuropathy.
99013. Autosomal recessive spastic paraplegia type 7.

PharmGKB

PA36067.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0465.

HOGENOM

HOG000217277.

HOVERGEN

HBG050184.

InParanoid

Q9UQ90.

KO

K09552.

OMA

MMDHEAK.

OrthoDB

EOG4PG60F.

PhylomeDB

Q9UQ90.

Gene expression databases

ArrayExpress

Q9UQ90.

Bgee

Q9UQ90.

CleanEx

HS_SPG7.

Genevestigator

Q9UQ90.

GermOnline

ENSG00000197912. Homo sapiens.

Family and domain databases

InterPro

IPR003593. AAA+_ATPase.
IPR003959. ATPase_AAA_core.
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.

ProtoNet

Search...

Other

ChiTaRS

SPG7. human.

EvolutionaryTrace

Q9UQ90.

GenomeRNAi

6687.

NextBio

26057.

SOURCE

Search...

Entry information

Entry name

SPG7_HUMAN

Accession

Primary (citable) accession number: Q9UQ90
Secondary accession number(s): O75756 , Q2TB70, Q58F00, Q96IB0

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	October 17, 2006
Last modified:	May 29, 2013
This is version 134 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.