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akap1

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Official Full Name
A kinase (PRKA) anchor protein 1
Background
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein binds to type I and type II regulatory subunits of PKA and anchors them to the mitochondrion. This protein is speculated to be involved in the cAMP-dependent signal transduction pathway and in directing RNA to a specific cellular compartment.
Synonyms
AKAP1; A kinase (PRKA) anchor protein 1; PRKA1; A-kinase anchor protein 1, mitochondrial; AKAP84; AKAP121; AKAP149; D AKAP1; dual specificity A kinase anchoring protein 1; PPP1R43; protein kinase anchoring protein 1; protein phosphatase 1; regulatory subunit 43; S AKAP84; SAKAP84; A kinase anchor protein; AKAP 149; AKAP; DAKAP1; Protein kinase A1; D-AKAP-1; A-kinase anchor protein 149 kDa; protein kinase A anchoring protein 1; spermatid A-kinase anchor protein 84; protein phosphatase 1, regulatory subunit 43; dual-specificity A-kinase anchoring protein 1; D-AKAP1

The A kinase anchoring proteins (AKAPs) family is a group of functionally related proteins that bind to protein kinase (PK) A. AKAP1 is the first protein found in the AKAP family, which is mainly localized to the mitochondrial outer membrane. It plays an important regulatory role in the mitochondrial morphological structure and functional homeostasis.

AKAP1 is widely expressed in various organ tissues such as heart, liver, kidney, skeletal muscle, and brain. It can form a variety of different alternative splicing bodies. The N-terminal exon region of the AKPA1 gene encodes a targeting sequence localized to the mitochondria. The mitochondrial localization sequence is introduced into the mitochondria through the mitochondrial outer membrane translocator complex, which is then released into the mitochondrial inner membrane, becoming a transmembrane anchor site, anchoring the AKA1 protein to the mitochondria, while the rest of the protein is exposed in the cytoplasm. In addition, the study found that there is an NI splicing of AKAP1 protein in mouse, which contains 33 additional amino acid residues in its structure. The N-terminal exon sequence of this splice can target AKAP1 to the endoplasmic reticulum. However, the N-terminal exon sequence is not conserved. Currently, the exon contains a promoter only in mice, while the N-terminal exon sequence of the N1 splice of the AKAP1 protein in other species does not contain a promoter. The most abundant and most characteristic product of the AKAP1 gene is the full-length AKAP1 splice.

Figure 1. The mitochondrial signalosome.(Monterisi., et al. 2017)

Monterisi et al. identified mitochondrial phosphopeptides of 100 potential PKA targets by mass spectrometry in proteins of the mitochondria. AKAP1 was the first to be discovered; its N-terminal domain contains the functional tubulin binding motif necessary for mitochondrial localization.

AKAP1 Interacts with Proteins

AKAP1 recruits a variety of signaling proteins and mRNAs to the mitochondrial outer membrane to form a signal complex that regulates cellular processes. As a member of the AKAPs family, AKAP1 anchors PRA to the mitochondrial outer membrane and promotes phosphorylation of downstream PRA substrates. Studies have shown that overexpression of AKAP in PC12 neurons activates the mitochondrial cAMP/PKA signaling pathway. Further, PRA phosphorylates the pro-apoptotic protein BAD (Bcl-2-associated deathpromoter) and inhibits the release of mitochondrial cytochrome c, thereby reducing Apoptosis.

In contrast, AKAPI also binds to type 4 phosphodiesterases (PDE4), whereas PDE4 inhibits PRA activity by hydrolyzing cAMP, suggesting that AKAPI regulation of PRA may be significantly different depending on intracellular and external environmental differences. Scorziello et al. found that AKAP1 in neurons can directly bind to the mitochondrial Na2+/Ca2+ exchanger mNCX3, maintaining mitochondrial calcium homeostasis. AKAP1 in cardiomyocytes can recruit calcineurin CaN and inhibit cardiomyocyte hypertrophy. Rinaldi et al. found that AKAP1 in tumor cells can bind to the highly conserved stress response protein Sestrin2 to regulate mTOR signaling and mediate tumorigenesis.

AKAP1 Interacts with RNA

The study found that AKAP1 has an RNA-binding motif (KH domain), suggesting that it may be involved in RNA degradation, mRNA transcription, and translational regulation by directing RNA to specific subcellular regions through binding to RNA. The KH domain of the C-terminus of the AKAP1 protein has a binding site composed of two helices, one GXXG loop and one β-sheet, and AKAP1 can bind to the 3'-UTR end of a specific RNA through the binding site. The AKAP1-binding RNAs that have been found to include the subunits that produce the ATP synthase Fo complex, manganese superoxide (MnSOD), and steroidogenic acute regulatory (STAR) mRNAs. AKAP1 localizes these mRNAs to the mitochondrial outer membrane and regulates its translation. For example, studies have shown that AKAP1 overexpression can increase the level of MnSOD in mitochondria. Conversely, translation of lipoprotein lipase (LPL)-associated mRNA with AKAP1 inhibits LPL translation via a PRA-dependent molecular mechanism.

Upstream Regulation Mechanism of AKAP1

Schiattarella et al. found that AKAP1 expression levels were significantly reduced in cardiomyocytes after exposure of cardiomyocytes to hypoxic conditions (2-4 h). Under hypoxic conditions, intracellular E3 ubiquitination SIAH (seven in absentia homolog) 2 binds to AKAP1 and rapidly degrades AKAPI through a phosphorylation/ubiquitination pathway. Some scholars believe that SIAH2 molecule-mediated AKAPI degradation can attenuate mitochondrial metabolic activities, enabling ischemic tissue to rapidly adapt to metabolic levels under hypoxic conditions, thereby facilitating tissue survival in hypoxic conditions. Tsushima et al. showed that the ubiquitin/proteasome system pathway in the high-fat state can degrade AKAPI at the post-translational level and cause variable phosphorylation of dynamin-related protein (Drp)1 protein, while translating SIAH2 The level of related mRNA molecules did not increase, suggesting that the down-regulation of AKAP1 in the high-fat state is different from the down-regulation of AKAP1 in the hypoxic state and the two are independent two signaling pathways.

AKAP1 Maintains Mitochondrial Homeostasis

In mammalian cells, when cells are in desperate need of energy supply, the body activates the AMP/PRA signaling pathway, thereby promoting mitochondrial energy production and synthesis. Studies have shown that AKAP1 can anchor PRA specific to the mitochondrial outer membrane and spatially close the distance between PRA and its mitochondrial substrate, such as the subunit NDUFS4C of mitochondrial complex 1. Once the intracellular cAMP concentration is increased, PRA activation rapidly phosphorylates NDUFS4 and other related mitochondrial complex subunits, thereby promoting mitochondrial oxidative respiratory chain activity. AKAP1 can also target Src to mitochondria. In HEK293 cells, mitochondrial Src phosphorylates cyclooxygenase (COX) via PTPD1 and promotes ATP synthesis. Thus, the cAMP/PKA signaling pathway and the tyrosine kinase Src signaling pathway in the mitochondria are "conversed" by the AKA1 molecule. These studies suggest that AKAP1 molecules can integrate different signaling pathways and play an important role in the regulation of mitochondrial oxidative respiration.

Mitochondrial division and fusion play an important role in cellular metabolic homeostasis and stress impairment responses. Proteins involved in mitochondrial division in mammalian cells mainly include Drpl and its receptor protein. Activated PKA is capable of phosphorylating the Drpl serine 637 site and inhibiting Drpl activity, thereby promoting mitochondrial fusion. It was found that as an anchor protein of PRA, AKAP1 can accelerate the process of phosphorylation of Drp1 by regulating mitochondrial microenvironment. Moreover, AKAP1 can inhibit the formation of Drp1/FIS1 complex and inhibit mitochondrial division. Further, the researchers found that under hypoxic conditions, elevated SIAH2 activity promotes ubiquitination and degradation of AKAPI, thereby promoting Drp1/FIS1-mediated mitochondrial division, down-regulation of oxidative phosphorylation, finally resulting in cell damage and apoptosis. These findings suggest that AKAPI plays a crucial role in the regulation of mitochondrial mediated apoptosis and adaptation to hypoxic conditions under hypoxic conditions.

References:

  1. Scorziello, A., Savoia, C., Sisalli, M. J., Adornetto, A., Secondo, A., & Boscia, F., et al. (2013). Ncx3 regulates mitochondrial ca(2+) handling through the akap121-anchored signaling complex and prevents hypoxia-induced neuronal death. Journal of Cell Science, 126(24), 5566-5577.
  2. Rinaldi, L., Sepe, M., Delle, D. R., Conte, K., Arcella, A., & Borzacchiello, D., et al. (2017). Mitochondrial akap1 supports mtor pathway and tumor growth. Cell Death & Disease, 8(6), e2842.
  3. Schiattarella, G. G., Cattaneo, F., Pironti, G., Magliulo, F., Carotenuto, G., & Pirozzi, M., et al. (2016). Akap1 deficiency promotes mitochondrial aberrations and exacerbates cardiac injury following permanent coronary ligation via enhanced mitophagy and apoptosis. Plos One, 11(5), e0154076.
  4. Monterisi, S., & Zaccolo, M. (2017). Components of the mitochondrial camp signalosome. Biochemical Society Transactions, 45(1), 269.
  5. Tsushima, K., Bugger, H., Wende, A. R., Soto, J., Jenson, G. A., & Tor, A. R., et al. (2017). Mitochondrial reactive oxygen species in lipotoxic hearts induces post-translational modifications of akap121, drp1 and opa1 that promote mitochondrial fission. Circulation Research, 122(1), CIRCRESAHA.117.311307.
  6. Kiriyama, Y., & Nochi, H. (2017). Intra- and intercellular quality control mechanisms of mitochondria. Cells, 7(1).