| SPG7 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Paraplegin is a protein that in humans is encoded by the SPG7 gene located on chromosome 16. [5] [6] [7]
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]
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.
SPG7 interacts with AFG like AAA ATPase 2 (AFG3L2) on the mitochondrial inner membrane to form the m-AAA metalloproteinase complex.
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]
Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease. The symptoms are a result of dysfunction of long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease. HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to treat HSP symptoms.
Vacuolar-type ATPase (V-ATPase) is a highly conserved evolutionarily ancient enzyme with remarkably diverse functions in eukaryotic organisms. V-ATPases acidify a wide array of intracellular organelles and pumps protons across the plasma membranes of numerous cell types. V-ATPases couple the energy of ATP hydrolysis to proton transport across intracellular and plasma membranes of eukaryotic cells. It is generally seen as the polar opposite of ATP synthase because ATP synthase is a proton channel that uses the energy from a proton gradient to produce ATP. V-ATPase however, is a proton pump that uses the energy from ATP hydrolysis to produce a proton gradient.
The human gene SPAST codes for the microtubule-severing protein of the same name, commonly known as spastin.
Atlastin, or Atlastin-1, is a protein that in humans is encoded by the ATL1 gene.
Transmembrane protease, serine 3 is an enzyme that in humans is encoded by the TMPRSS3 gene.
Spartin is a protein that in humans is encoded by the SPG20 gene.
Sacsin also known as DnaJ homolog subfamily C member 29 (DNAJC29) is a protein that in humans is encoded by the SACS gene. Sacsin is a Hsp70 co-chaperone.
Kinesin heavy chain isoform 5A is a protein that in humans is encoded by the KIF5A gene.
Non-imprinted in Prader-Willi/Angelman syndrome region protein 1 is a protein that in humans is encoded by the NIPA1 gene. This gene encodes a potential transmembrane protein which functions either as a receptor or transporter molecule, possibly as a magnesium transporter. This protein is thought to play a role in nervous system development and maintenance. Alternative splice variants have been described, but their biological nature has not been determined. Mutations in this gene have been associated with the human genetic disease autosomal dominant spastic paraplegia 6.
ATP-dependent metalloprotease YME1L1 is an enzyme that in humans is encoded by the YME1L1 gene. YME1L1 belongs to the AAA family of ATPases and mainly functions in the maintenance of mitochondrial morphology. Mutations in this gene would cause infantile-onset mitochondriopathy.
Phenylalanyl-tRNA synthetase, mitochondrial (FARS2) is an enzyme that in humans is encoded by the FARS2 gene. This protein encoded by FARS2 localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 14, also known as Alpers encephalopathy, as well as spastic paraplegia 77 and infantile-onset epilepsy and cytochrome c oxidase deficiency.
Spatacsin is a protein that in humans is encoded by the SPG11 gene.
AFG3 ATPase family gene 3-like 2 is a protein that in humans is encoded by the AFG3L2 gene.
Fatty acid 2-hydroxylase is a protein that in humans is encoded by the FA2H gene.
Acetyl-coenzyme A transporter 1 also known as solute carrier family 33 member 1 (SLC33A1) is a protein that in humans is encoded by the SLC33A1 gene.
Zinc finger, FYVE domain containing 26 is a protein that in humans is encoded by the ZFYVE26 gene.
Spastic paraplegia 15 (SPG15) is a form of hereditary spastic paraplegia that commonly becomes apparent during childhood or adolescence. The disease is caused by mutations within the ZFYVE26 gene - also known as the SPG15 gene - and is passed down in an autosomal recessive manner.
AP-5 complex subunit beta (AP5B1) is a protein that in humans is encoded by the AP5B1 gene.
AP-5 complex subunit mu (AP5M1) is a protein that in humans is encoded by the AP5M1 gene.
AP-5 complex subunit sigma (AP5S1) is a protein that in humans is encoded by the AP5S1 gene.
