Paraplegin

Spastic paraplegia 7 (pure and complicated autosomal recessive)
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2QZ4​
Identifiers
Symbols	SPG7 ; CAR; CMAR; PGN; SPG5C
External IDs	OMIM: 602783 MGI: 2385906 HomoloGene: 31133 GeneCards: SPG7 Gene
Gene ontology Molecular function • metalloendopeptidase activity • protein binding • ATP binding • peptidase activity • zinc ion binding • unfolded protein binding Cellular component • mitochondrion • integral component of membrane • mitochondrial membrane Biological process • proteolysis • mitochondrion organization • nervous system development • anterograde axon cargo transport Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6687	234847
Ensembl	ENSG00000197912	ENSMUSG00000000738
UniProt	Q9UQ90	Q3ULF4
RefSeq (mRNA)	NM_003119	NM_153176
RefSeq (protein)	NP_003110	NP_694816
Location (UCSC)	Chr 16: 89.49 – 89.56 Mb	Chr 8: 123.06 – 123.1 Mb
PubMed search

Paraplegin is a protein that in humans is encoded by the SPG7 gene located on chromosome 16.^[1][2][3]

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.^[4]

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.^[5][6][7]

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.^[8] 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.^[9] 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.^[10]

References

1. Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A (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.
2. De Michele G, De Fusco M, Cavalcanti F, Filla A, Marconi R, Volpe G, Monticelli A, Ballabio A, Casari G, Cocozza S (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.
3. "Entrez Gene: SPG7 spastic paraplegia 7, paraplegin (pure and complicated autosomal recessive)".
4. Karlberg T, van den Berg S, Hammarström M, Sagemark J, Johansson I, Holmberg-Schiavone L, Schüler H (2009). "Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7". PLoS ONE 4 (10): e6975. doi:10.1371/journal.pone.0006975. PMC 2734466. PMID 19841671.
5. Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, Fawcett K, Sims D, Eglon G, Hadjivassiliou M, Horvath R, Németh A, Chinnery PF (2015). "SPG7 mutations are a common cause of undiagnosed ataxia". Neurology 84 (11): 1174–6. doi:10.1212/WNL.0000000000001369. PMC 4371411. PMID 25681447.
6. Warnecke T, Duning T, Schirmacher A, Mohammadi S, Schwindt W, Lohmann H, Dziewas R, Deppe M, Ringelstein EB, Young P (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.
7. Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A (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.
8. 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.
9. Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC, Mahmoud AB, Ho T, Stewart NA, Rippstein P, Harper ME, Roberts R, Willenborg C, Erdmann J, Pastore A, McBride HM, Langer T, Stewart AF (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.
10. Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF (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.

Further reading

• Pullman WE, Bodmer WF (Apr 1992). "Cloning and characterization of a gene that regulates cell adhesion". Nature 356 (6369): 529–32. doi:10.1038/356529a0. PMID 1560826.
• Koyama K, Emi M, Nakamura Y (Apr 1993). "The cell adhesion regulator (CAR) gene, TaqI and insertion/deletion polymorphisms, and regional assignment to the peritelomeric region of 16q by linkage analysis". Genomics 16 (1): 264–5. doi:10.1006/geno.1993.1173. PMID 8098008.
• Pullman WE, Bodmer WF (Feb 1993). "Cloning and characterization of a gene that regulates cell adhesion". Nature 361 (6412): 564. doi:10.1038/361564c0. PMID 8429914.
• Durbin H, Novelli MR, Bodmer WF (Dec 1997). "Genomic and cDNA sequence analysis of the cell matrix adhesion regulator gene". Proceedings of the National Academy of Sciences of the United States of America 94 (26): 14578–83. doi:10.1073/pnas.94.26.14578. PMC 25060. PMID 9405655.
• Settasatian C, Whitmore SA, Crawford J, Bilton RL, Cleton-Jansen AM, Sutherland GR, Callen DF (1999). "Genomic structure and expression analysis of the spastic paraplegia gene, SPG7". Human Genetics 105 (1-2): 139–44. doi:10.1007/s004390051076. PMID 10480368.
• Kremmidiotis G, Gardner AE, Settasatian C, Savoia A, Sutherland GR, Callen DF (Aug 2001). "Molecular and functional analyses of the human and mouse genes encoding AFG3L1, a mitochondrial metalloprotease homologous to the human spastic paraplegia protein". Genomics 76 (1-3): 58–65. doi:10.1006/geno.2001.6560. PMID 11549317.
• McDermott CJ, Roberts D, Tomkins J, Bushby KM, Shaw PJ (Jun 2003). "Spastin and paraplegin gene analysis in selected cases of motor neurone disease (MND)". Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 4 (2): 96–9. doi:10.1080/14660820310012718. PMID 14506940.
• Pirozzi M, Quattrini A, Andolfi G, Dina G, Malaguti MC, Auricchio A, Rugarli EI (Jan 2006). "Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia". The Journal of Clinical Investigation 116 (1): 202–8. doi:10.1172/JCI26210. PMC 1312020. PMID 16357941.
• Elleuch N, Depienne C, Benomar A, Hernandez AM, Ferrer X, Fontaine B, Grid D, Tallaksen CM, Zemmouri R, Stevanin G, Durr A, Brice A (Mar 2006). "Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia". Neurology 66 (5): 654–9. doi:10.1212/01.wnl.0000201185.91110.15. PMID 16534102.
• Warnecke T, Duning T, Schwan A, Lohmann H, Epplen JT, Young P (Jul 2007). "A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation". Neurology 69 (4): 368–75. doi:10.1212/01.wnl.0000266667.91074.fe. PMID 17646629.

External links

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