# SPG7

## Overview
SPG7 is a gene located on chromosome 16 in humans that encodes the protein paraplegin, a mitochondrial metalloprotease belonging to the AAA protein family. Paraplegin is a critical component of the mitochondrial m-AAA protease complex, which plays a vital role in maintaining mitochondrial function by regulating the degradation of proteins within the mitochondria. This protease complex is essential for the proper functioning of the respiratory chain and other mitochondrial processes. Mutations in the SPG7 gene are associated with autosomal recessive hereditary spastic paraplegia type 7 (SPG7), a neurodegenerative disorder characterized by progressive stiffness and contraction of the lower limbs, and sometimes linked to other complex neurological symptoms (Almontashiri2014SPG7; Casari1998Spastic). The protein's involvement in mitochondrial dynamics and its interaction with other mitochondrial proteins underscore its importance in cellular energy metabolism and neurological health.

## Structure
Paraplegin, encoded by the SPG7 gene, is a mitochondrial metalloprotease and part of the AAA protein family, which is characterized by its ATPase activity. The protein structure of paraplegin includes several functional domains crucial for its activity. These include an ATP-binding motif (GPPGCGKT), a zinc-dependent binding domain (HEXXH), and the AAA minimal consensus sequence, which are conserved across similar yeast mitochondrial proteins (Settasatian1999Genomic; Casari1998Spastic). The protein also contains a conserved AAA-ATPase module spanning amino acid residues 341-481, characteristic of all known subunits of AAA proteases (Arnoldi2008A).

Paraplegin forms part of the m-AAA protease complex, functioning in hetero-oligomeric assemblies with the homologous AFG3L2 subunit, which suggests a quaternary structure involving multiple subunits (Arnoldi2008A). This complex is involved in various cellular activities including proteolytic and chaperone-like functions, essential for ribosome assembly and mitochondrial translation (Arnoldi2008A).

Details on the primary, secondary, and tertiary structures of paraplegin are not explicitly provided in the available literature. Similarly, information on prominent folds, common post-translational modifications, and splice variant isoforms is not detailed in the provided excerpts.

## Function
The SPG7 gene encodes paraplegin, a protein that is a critical component of the mitochondrial m-AAA protease complex located in the inner mitochondrial membrane. This complex is essential for maintaining mitochondrial function and integrity by regulating the degradation of damaged and surplus proteins, primarily those associated with the respiratory chain complexes (Levytskyy2016Mitochondrial). Paraplegin, in conjunction with the homologous subunit AFG3L2, forms oligomeric complexes that are crucial for the proteolytic activity necessary for the maturation of several mitochondrial proteins, including components of the mitochondrial translation machinery (Levytskyy2016Mitochondrial).

Paraplegin is also involved in the mitochondrial unfolded protein response (UPRmt), where its expression is upregulated during proteostatic stress to manage protein folding within the mitochondria (Levytskyy2016Mitochondrial). Additionally, it plays a role in the assembly and stability of respiratory complexes, which are integral to mitochondrial energy production and overall cellular health (Levytskyy2016Mitochondrial).

Mutations in the SPG7 gene, leading to dysfunctional paraplegin, result in hereditary spastic paraplegia (HSP), characterized by complex I deficiency and increased sensitivity to oxidative stress, underscoring the protein's importance in cellular energy production and resistance to oxidative damage (Atorino2003Loss).

## Clinical Significance
Mutations in the SPG7 gene, which encodes the protein paraplegin, are primarily associated with autosomal recessive hereditary spastic paraplegia type 7 (SPG7). This condition is characterized by progressive stiffness and contraction of the lower limbs, often accompanied by additional neurological symptoms such as cerebellar ataxia, optic neuropathy, and ophthalmoplegia. The clinical presentation can vary significantly, with symptoms onset ranging from early to mid-adulthood (Klebe2012Spastic; Coarelli2019Loss).

Research has also linked SPG7 mutations to other complex neurological disorders. For instance, some studies have identified a connection between SPG7 mutations and mitochondrial parkinsonism, characterized by symptoms such as bradykinesia, tremor, and rigidity (De2019Parkinsonism). Additionally, a subset of patients with SPG7 mutations exhibit features of chronic progressive external ophthalmoplegia, a condition involving gradual weakening of the eye muscles (Pfeffer2014Mutations).

Interestingly, heterozygous mutations in SPG7 have been associated with autosomal dominant optic neuropathy in specific cases, suggesting a potential dominant effect of some mutations (Klebe2012Spastic). Moreover, the gene's mutations have been implicated in broader spectrums of neurodegenerative diseases, including links to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorders (Osmanovic2020SPG7). These findings underscore the diverse impact of SPG7 mutations on neurological health and disease.

## Interactions
SPG7, also known as paraplegin, is involved in several critical protein interactions that are essential for mitochondrial function. It forms a part of the m-AAA protease complex in the mitochondrial inner membrane, interacting closely with AFG3L2. This interaction is crucial for the proteolytic processing of SPG7 to its mature form, which is necessary for the proper functioning of the m-AAA protease complex in regulating mitochondrial ribosome synthesis and degrading damaged proteins (Almontashiri2014SPG7).

The Q688 variant of SPG7, which replaces arginine at position 688 with glutamine, shows altered interactions compared to the common form. This variant forms a more stable heterohexameric complex with AFG3L2, potentially through a salt bridge formation involving the Q688 residue. This stability enhances the activity of the m-AAA protease, leading to increased processing of mitochondrial proteins such as Mrpl32 and elevated levels of mitochondrial respiratory chain components (Almontashiri2014SPG7).

Additionally, SPG7 interacts with cyclophilin D (CypD) as part of the mitochondrial permeability transition pore (PTP), a complex that plays a significant role in mitochondrial membrane potential dissipation and cell death under stress conditions (Shanmughapriya2016SPG7). These interactions underscore the multifaceted role of SPG7 in mitochondrial dynamics and cellular homeostasis.


## References


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[9. (Shanmughapriya2016SPG7) Santhanam Shanmughapriya, Sudarsan Rajan, Nicholas E. Hoffman, Dhanendra Tomar, Neeharika Nemani, and Muniswamy Madesh. Spg7 is an essential and conserved component of the mitochondrial permeability transition pore. Biophysical Journal, 110(3):309a–310a, February 2016. URL: http://dx.doi.org/10.1016/j.bpj.2015.11.1663, doi:10.1016/j.bpj.2015.11.1663. (207 citations) 10.1016/j.bpj.2015.11.1663](https://doi.org/10.1016/j.bpj.2015.11.1663)

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