The reference OMIM entry for this protein is 604581

Atpase family gene 3-like 2; afg3l2

DESCRIPTION

AFG3L2 is the catalytic subunit of the m-AAA protease, an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly (summary by Koppen et al., 2007).

CLONING

By searching an EST database with the sequence of paraplegin (SPG7; 602783) and screening a fetal brain cDNA library, Banfi et al. (1999) identified a cDNA for AFG3L2. AFG3L2 encodes a deduced 797-amino acid protein whose sequence shows 69% similarity to the yeast Afg3 mitochondrial ATPase and 49% identity to paraplegin. AFG3L2 contains an AAA (for ATPase associated with diverse cellular activities) domain of about 190 amino acids with an ATP/GTP-binding site, a zinc-dependent binding domain, and an RNA-binding region. Northern blot analysis revealed that AFG3L2 is expressed ubiquitously as a 3.2-kb transcript in fetal and adult tissues, with greatest expression in heart and skeletal muscle. Fluorescence microscopy showed that AFG3L2 is localized in mitochondria. Thus, AFG3L2 and paraplegin share a similar expression pattern and the same localization.

GENE STRUCTURE

Di Bella et al. (2010) noted that the AFG3L2 gene contains 17 exons spanning 48 kb.

MAPPING

By radiation hybrid analysis, Banfi et al. (1999) mapped the AFG3L2 gene to chromosome 18p11. Di Bella et al. (2010) noted that the AFG3L2 gene maps to chromosome 18p11.21.

GENE FUNCTION

Using in vitro protein binding assays and immunoprecipitation analysis, Koppen et al. (2007) showed that paraplegin interacted with AFG3L2 in the m-AAA protease complex. AFG3L2 also interacted with itself. Loss of paraplegin in Spg7 -/- mice or in SPG7 patient fibroblasts resulted in m-AAA protease complexes made up of only homodimerized AFG7L2 that were proteolytically active against misfolded mitochondrial membrane proteins in yeast complementation assays. Di Bella et al. (2010) found expression of the AFG3L2 gene in Purkinje cell bodies and dendrites of the human cerebellum and in large neurons of the deep cerebellar layer. AFG3L2 and paraplegin were also expressed in pyramidal cortical neurons and spinal motor neurons. Similar expression was found in mouse tissues.

MOLECULAR GENETICS

- Spinocerebellar Ataxia 28, Autosomal Dominant In affected members of 5 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Di Bella et al. (2010) identified 5 different heterozygous mutations in the AFG3L2 gene (604581.0001-604581.0005). Studies in yeast showed that the mutations affected respiratory and proteolytic functions of the protein by both dominant-negative (E691K; 604581.0001), and loss-of-function (see, e.g., S674L, 604581.0002) mechanisms. Di Bella et al. (2010) hypothesized that AFG3L2 or specific substrates of AFG3L2 may have an essential function in protecting the cerebellum from neurodegeneration. Cagnoli et al. (2010) identified 6 different missense mutations in exons 15 and 16 of the AFG3L2 gene (see, e.g., 604581.0006-604581.0009) in 9 (2.6%) of 366 Caucasian European probands with autosomal dominant SCA who were negative for the most common triplet expansions in other genes. All mutations affected the highly conserved C-terminal peptidase-M41 domain and were predicted to destabilize the AFG3L2 complex. Pathogenic copy number variations affecting the AFG3L2 gene were not detected. - Spastic Ataxia 5, Autosomal Recessive By whole-exome sequencing of 2 brothe ... More on the omim web site

Subscribe to this protein entry history

July 1, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

June 29, 2020: Protein entry updated
Automatic update: OMIM entry 604581 was added.

Jan. 22, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).