# ATPAF2

## Overview
ATPAF2 is a gene that encodes the ATP synthase mitochondrial F1 complex assembly factor 2, a crucial protein involved in the assembly of the mitochondrial ATP synthase complex. This protein functions as a chaperone-like assembly factor, facilitating the integration of the α subunit into the F1-ATPase component of ATP synthase, which is essential for cellular energy production through oxidative phosphorylation. ATPAF2 is predominantly active in the mitochondrial matrix and is particularly expressed in tissues with high mitochondrial content, such as brown adipose tissue. Mutations in the ATPAF2 gene can lead to severe mitochondrial disorders, highlighting its critical role in maintaining mitochondrial function and energy metabolism (Pı́cková2003Differential; Tauchmannová2024Variability; HEJZLAROVÁ2014Nuclear).

## Structure
The ATPAF2 protein, also known as ATP synthase mitochondrial F1 complex assembly factor 2, plays a crucial role in the assembly of the mitochondrial ATP synthase complex. The structure of ATPAF2 includes a small 3-stranded β-sheet at the N-terminus, while the remainder of the protein is predominantly α-helical (Pei2021Human). The interaction site on ATPAF2 is located on the last α-helix, which contains a residue with a pathogenic mutation (L262P) (Pei2021Human). This mutation is reported in the ClinVar database and is associated with potential pathogenic effects.

ATPAF2 is an assembly factor essential for incorporating the α subunit into the F1-ATPase structure. A specific mutation, c.280T>A, results in the replacement of tryptophan with arginine at position 94, affecting the protein's interaction with the α subunit and leading to aggregation, which disrupts ATP synthase assembly (HEJZLAROVÁ2014Nuclear). This mutation impacts the solubility of ATPAF2, causing it to aggregate and disrupt ATP synthase assembly (HEJZLAROVÁ2014Nuclear). The protein's interaction with other mitochondrial proteins, such as FMC1, has been validated experimentally and supported by high contact probabilities from computational models (Pei2021Human).

## Function
The ATPAF2 gene encodes a mitochondrial protein that plays a crucial role in the assembly of the F1-ATPase component of ATP synthase, a key enzyme in cellular energy production. This protein, known as Atpaf2p, functions as an assembly factor by interacting with the K subunit of the F1-ATPase, facilitating its proper folding and integration into the ATP synthase complex (Pı́cková2003Differential). ATPAF2 is active in the mitochondrial matrix, where it impacts energy metabolism and cellular respiration by ensuring the efficient synthesis of ATP during oxidative phosphorylation (Pı́cková2003Differential).

The expression of ATPAF2 varies significantly across different tissues, with the highest levels observed in brown adipose tissue. This suggests that ATPAF2 may regulate the mitochondrial content of ATPase, particularly in tissues with high mitochondrial content but low ATPase levels (Pı́cková2003Differential). The gene's expression is correlated with the mRNA levels of the F1-KK and F1-LL subunits, indicating a shared regulatory mechanism (Pı́cková2003Differential). ATPAF2, along with ATPAF1, is generally present in eukaryotes and may exhibit chaperone-like activity, similar to its yeast orthologues (Pı́cková2003Differential).

## Clinical Significance
Mutations in the ATPAF2 gene are associated with severe mitochondrial disorders, primarily affecting the assembly of the mitochondrial ATP synthase complex. A notable mutation, c.280T>A, results in the substitution of tryptophan with arginine at position 94 (p.Trp94Arg). This mutation has been linked to severe neonatal encephalopathy, characterized by cortical and subcortical brain atrophy, basal ganglia atrophy, and metabolic acidosis. Patients with this mutation often exhibit dysmorphic features and may experience early mortality, as seen in a case where the affected individual died at 14 months (Mayr2010Mitochondrial; Tauchmannová2024Variability).

The mutation leads to a significant reduction in the levels of fully assembled complex V, without the accumulation of subassembly intermediates, indicating a critical disruption in ATP synthase assembly (Ghezzi2018Human). This deficiency results in decreased ATP hydrolytic activity, contributing to the clinical manifestations of the disease, such as encephalopathy, lactic acidosis, and 3-methylglutaconic aciduria (Tauchmannová2024Variability). The clinical significance of ATPAF2 mutations underscores the gene's essential role in mitochondrial function and energy production, particularly in tissues with high energy demands like the brain (Tauchmannová2024Variability).

## Interactions
ATPAF2, also known as ATP synthase mitochondrial F1 complex assembly factor 2, is involved in the assembly of the mitochondrial ATP synthase complex. It interacts with FMC1, a member of the LYRM family of proteins, which is crucial for the assembly of the ATP synthase F1 complex. This interaction was predicted using computational tools and validated experimentally, with high contact probabilities reported by AlphaFold2 and RoseTTAFold (Pei2021Human). The interaction site on ATPAF2 is mapped to the last α-helix, which includes a residue with a likely pathogenic mutation (L262P) (Pei2021Human).

ATPAF2 is also noted for its role in the initial formation of the F1 assembly, which is essential for the addition of other subunits in the ATP synthase complex (Mayr2010Mitochondrial). While specific interactions with other proteins are not detailed, ATPAF2 is recognized as a nuclear-encoded mitochondrial chaperone protein necessary for assembling the F1 sector of ATP synthase (Zhou2021ATPAF1). The importance of ATPAF2 in ATP synthase assembly is underscored by the severe impact of its deficiency in yeast and mice, highlighting its critical role in mitochondrial function (Zhou2021ATPAF1).


## References


[1. (HEJZLAROVÁ2014Nuclear) K. HEJZLAROVÁ, T. MRÁČEK, M. VRBACKÝ, V. KAPLANOVÁ, V. KARBANOVÁ, H. NŮSKOVÁ, P. PECINA, and J. HOUŠTĚK. Nuclear genetic defects of mitochondrial atp synthase. Physiological Research, pages S57–S71, February 2014. URL: http://dx.doi.org/10.33549/PHYSIOLRES.932643, doi:10.33549/physiolres.932643. This article has 60 citations and is from a peer-reviewed journal.](https://doi.org/10.33549/PHYSIOLRES.932643)

[2. (Tauchmannová2024Variability) K Tauchmannová, A Pecinová, J Houštěk, and T Mráček. Variability of clinical phenotypes caused by isolated defects of mitochondrial atp synthase. 70th Anniversary of the Institute of Physiology, pages S243–S278, August 2024. URL: http://dx.doi.org/10.33549/physiolres.935407, doi:10.33549/physiolres.935407. This article has 0 citations.](https://doi.org/10.33549/physiolres.935407)

[3. (Pı́cková2003Differential) Andrea Pı́cková, Jan Paul, Vittoria Petruzzella, and Josef Houštěk. Differential expression of atpaf1 and atpaf2 genes encoding f1‐atpase assembly proteins in mouse tissues. FEBS Letters, 551(1–3):42–46, August 2003. URL: http://dx.doi.org/10.1016/s0014-5793(03)00890-1, doi:10.1016/s0014-5793(03)00890-1. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/s0014-5793(03)00890-1)

[4. (Zhou2021ATPAF1) Zhou Zhou, Kailiang Zhang, Zhiheng Liu, Xu Gao, Kai Huang, Chen Chen, Daowen Wang, Qinglin Yang, and Qinqiang Long. Atpaf1 deficiency impairs atp synthase assembly and mitochondrial respiration. Mitochondrion, 60:129–141, September 2021. URL: http://dx.doi.org/10.1016/j.mito.2021.08.005, doi:10.1016/j.mito.2021.08.005. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.mito.2021.08.005)

5. (Pei2021Human) Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling. This article has 3 citations.

[6. (Ghezzi2018Human) Daniele Ghezzi and Massimo Zeviani. Human diseases associated with defects in assembly of oxphos complexes. Essays in Biochemistry, 62(3):271–286, July 2018. URL: http://dx.doi.org/10.1042/ebc20170099, doi:10.1042/ebc20170099. This article has 79 citations and is from a peer-reviewed journal.](https://doi.org/10.1042/ebc20170099)

[7. (Mayr2010Mitochondrial) J. A. Mayr, V. Havlickova, F. Zimmermann, I. Magler, V. Kaplanova, P. Jesina, A. Pecinova, H. Nuskova, J. Koch, W. Sperl, and J. Houstek. Mitochondrial atp synthase deficiency due to a mutation in the atp5e gene for the f1 subunit. Human Molecular Genetics, 19(17):3430–3439, June 2010. URL: http://dx.doi.org/10.1093/hmg/ddq254, doi:10.1093/hmg/ddq254. This article has 112 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddq254)