Paraplegin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''SPG7''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

located on chromosome 16.

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 X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

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 change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...

s to the AAA-domain in order to deliver the substrate peptides to be degraded to its protease core.

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 A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...

that is located to the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

, and is part of the m-AAA metalloproteinase complex, which constitutes one of the known intra- mitochondrial

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

s 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 A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

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. 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. 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. Furthermore, SPG7 deficiency is associated with abnormal

mitochondrial DNA Mitochondrial DNA (mtDNA and mDNA) is the DNA located in the mitochondrion, mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the D ...

maintenance, which may lead to secondary mitochondrial DNA lesions and impaired respiratory activities and mitochondrial functions.

References

External links