Paraplegin

SPG7
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2QZ4
Identifiers
Aliases	SPG7, CAR, CMAR, PGN, SPG5C, paraplegin matrix AAA peptidase subunit, SPG7 matrix AAA peptidase subunit, paraplegin
External IDs	OMIM: 602783; MGI: 2385906; HomoloGene: 31133; GeneCards: SPG7; OMA:SPG7 - orthologs
Gene location (Human)
Chr.	Chromosome 16 (human)
End	89,557,766 bp
Gene location (Mouse)
Chr.	Chromosome 8 (mouse)
End	123,824,499 bp
RNA expression pattern
	Top expressed in
	gonad; ; sural nerve; ; left lobe of thyroid gland; ; apex of heart; ; right lobe of thyroid gland; ; gastric mucosa; ; right hemisphere of cerebellum; ; anterior pituitary; ; left ovary; ; right ovary;
	Top expressed in
	neural layer of retina; ; spermatocyte; ; muscle of thigh; ; interventricular septum; ; spermatid; ; right kidney; ; superior frontal gyrus; ; lip; ; primary visual cortex; ; skeletal muscle tissue;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	unfolded protein binding; nucleotide binding; peptidase activity; zinc ion binding; metalloendopeptidase activity; protein binding; hydrolase activity; ATP binding; metallopeptidase activity; metal ion binding;
Cellular component	integral component of membrane; mitochondrion; membrane; mitochondrial inner membrane; mitochondrial permeability transition pore complex; m-AAA complex; axon cytoplasm;
Biological process	proteolysis; nervous system development; mitochondrial calcium ion transmembrane transport; regulation of mitochondrial membrane permeability; mitochondrial outer membrane permeabilization involved in programmed cell death; mitochondrion organization; anterograde axonal transport;
	Sources:Amigo / QuickGO
Orthologs
	6687
	234847
	ENSG00000197912
	ENSMUSG00000000738
	Q9UQ90
	Q3ULF4
	NM_003119; NM_199367; NM_001363850
	NM_153176; NM_001364435
	NP_003110; NP_955399; NP_001350779
	NP_694816; NP_001351364
	Wikidata
View/Edit Human	View/Edit Mouse

Paraplegin is a protein that in humans is encoded by the SPG7 gene located on chromosome 16.^[5]^[6]^[7]

Structure

The SPG7 gene contains 21 exons and encodes for a protein that is approximately 88 kDa in size. Two transcript variants encoding distinct isoforms have been identified for this gene.

The structure of the SPG7 resolved by X-ray crystallography reveals that the protein functions as a hexamer and is structurally most similar to bacterial FtSH proteases. It contains an FtsH-homology protease domain as well as an AAA+ homology ATPase domain. The protein is thought to use ATPase-driven conformational changes to the AAA-domain in order to deliver the substrate peptides to be degraded to its protease core.^[8]

Function

The SPG7 protein is a nuclear-encoded metalloprotease protein that is a member of the AAA protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The SPG7 protein is a transmembrane protein that is located to the inner mitochondrial membrane, and is part of the m-AAA metalloproteinase complex, which constitutes one of the known intra-mitochondrial proteases that function in mitochondrial protein quality control.

Interactions

SPG7 interacts with AFG like AAA ATPase 2 (AFG3L2) on the mitochondrial inner membrane to form the m-AAA metalloproteinase complex.

Clinical significance

Mutations associated with this gene cause autosomal recessive spastic paraplegia 7, a neurodegenerative disorder that is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG7 mutations have also been associated with other undiagnosed ataxia.^[9]^[10]^[11]

In model animals, knockdown of spastic paraplegia 7 by siRNA inhibits the early stages of HIV-1 replication in 293T cells infected with VSV-G pseudotyped HIV-1.^[12] It has been shown that an SPG7 variant escapes phosphorylation-regulated processing by AFG3L2 and increases mitochondrial reactive oxygen species generation and is correlated with many clinical phenotypes.^[13] Furthermore, SPG7 deficiency is associated with abnormal mitochondrial DNA maintenance, which may lead to secondary mitochondrial DNA lesions and impaired respiratory activities and mitochondrial functions.^[14]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000197912 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000000738 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, et al. (Jun 1998). "Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease". Cell. 93 (6): 973–83. doi:10.1016/S0092-8674(00)81203-9. PMID 9635427.
^ De Michele G, De Fusco M, Cavalcanti F, Filla A, Marconi R, Volpe G, et al. (Jul 1998). "A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3". American Journal of Human Genetics. 63 (1): 135–9. doi:10.1086/301930. PMC 1377251. PMID 9634528.
^ "Entrez Gene: SPG7 spastic paraplegia 7, paraplegin (pure and complicated autosomal recessive)".
^ Karlberg T, van den Berg S, Hammarström M, Sagemark J, Johansson I, Holmberg-Schiavone L, et al. (2009). "Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7". PLOS ONE. 4 (10): e6975. Bibcode:2009PLoSO...4.6975K. doi:10.1371/journal.pone.0006975. PMC 2734466. PMID 19841671.
^ Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, et al. (2015). "SPG7 mutations are a common cause of undiagnosed ataxia". Neurology. 84 (11): 1174–6. doi:10.1212/WNL.0000000000001369. PMC 4371411. PMID 25681447.
^ Warnecke T, Duning T, Schirmacher A, Mohammadi S, Schwindt W, Lohmann H, et al. (2010). "A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects". Mov. Disord. 25 (4): 413–20. doi:10.1002/mds.22949. PMID 20108356. S2CID 8667332.
^ Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, et al. (1998). "Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease". Cell. 93 (6): 973–83. doi:10.1016/s0092-8674(00)81203-9. PMID 9635427.
^ König R, Zhou Y, Elleder D, Diamond TL, Bonamy GM, Irelan JT, et al. (Oct 2008). "Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication". Cell. 135 (1): 49–60. doi:10.1016/j.cell.2008.07.032. PMC 2628946. PMID 18854154.
^ Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC, Mahmoud AB, et al. (2014). "SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes". Cell Rep. 7 (3): 834–47. doi:10.1016/j.celrep.2014.03.051. PMID 24767997.
^ Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, et al. (2014). "Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance". Brain. 137 (Pt 5): 1323–36. doi:10.1093/brain/awu060. PMC 3999722. PMID 24727571.

External links

GeneReviews/NCBI/NIH/UW entry on Spastic Paraplegia 7

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000197912 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000000738 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9635427-5] Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, et al. (Jun 1998). "Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease". Cell. 93 (6): 973–83. doi:10.1016/S0092-8674(00)81203-9. PMID 9635427.

[pmid9634528-6] De Michele G, De Fusco M, Cavalcanti F, Filla A, Marconi R, Volpe G, et al. (Jul 1998). "A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3". American Journal of Human Genetics. 63 (1): 135–9. doi:10.1086/301930. PMC 1377251. PMID 9634528.

[entrez-7] "Entrez Gene: SPG7 spastic paraplegia 7, paraplegin (pure and complicated autosomal recessive)".

[8] Karlberg T, van den Berg S, Hammarström M, Sagemark J, Johansson I, Holmberg-Schiavone L, et al. (2009). "Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7". PLOS ONE. 4 (10): e6975. Bibcode:2009PLoSO...4.6975K. doi:10.1371/journal.pone.0006975. PMC 2734466. PMID 19841671.

[9] Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, et al. (2015). "SPG7 mutations are a common cause of undiagnosed ataxia". Neurology. 84 (11): 1174–6. doi:10.1212/WNL.0000000000001369. PMC 4371411. PMID 25681447.

[10] Warnecke T, Duning T, Schirmacher A, Mohammadi S, Schwindt W, Lohmann H, et al. (2010). "A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects". Mov. Disord. 25 (4): 413–20. doi:10.1002/mds.22949. PMID 20108356. S2CID 8667332.

[11] Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, et al. (1998). "Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease". Cell. 93 (6): 973–83. doi:10.1016/s0092-8674(00)81203-9. PMID 9635427.

[12] König R, Zhou Y, Elleder D, Diamond TL, Bonamy GM, Irelan JT, et al. (Oct 2008). "Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication". Cell. 135 (1): 49–60. doi:10.1016/j.cell.2008.07.032. PMC 2628946. PMID 18854154.

[13] Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC, Mahmoud AB, et al. (2014). "SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes". Cell Rep. 7 (3): 834–47. doi:10.1016/j.celrep.2014.03.051. PMID 24767997.

[14] Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, et al. (2014). "Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance". Brain. 137 (Pt 5): 1323–36. doi:10.1093/brain/awu060. PMC 3999722. PMID 24727571.

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