Details for: AKAP3

Gene ID: 10566

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: AKAP3

Ensembl ID: ENSG00000111254

Description: A-kinase anchoring protein 3

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • ependymal cell CL0000065
    CSI 3.96
    rCSI 8.03%
    PRS 99.83

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary A-kinase anchoring protein 3 ([AKAP3](/details-gene/10566)) is a protein-coding gene that plays a critical role in male fertility. As an A-kinase anchoring protein (AKAP), its primary function is to bind the regulatory subunit of protein kinase A (PKA), thereby tethering the enzyme to specific subcellular locations. This scaffolding function is essential for the spatial and temporal regulation of PKA signaling. Consistent with this role, [AKAP3](/details-gene/10566) is a key structural component of the sperm flagellum, localized to the fibrous sheath, midpiece, and principal piece. Its involvement is crucial for processes such as sperm motility and the acrosome reaction. Loss-of-function mutations in [AKAP3](/details-gene/10566) have been identified as a cause of male infertility characterized by sperm with multiple morphological abnormalities ([Link](https://doi.org/10.1136/jmedgenet-2021-108271)). ## Cellular Roles and Expression Landscape **Overall**, while expression data analysis indicates a notable significance score for [AKAP3](/details-gene/10566) in [ependymal cell](/details-cell/CL0000065) (CSI: 3.96), a comprehensive review of its functional annotations and the existing literature overwhelmingly establishes its primary role as a sperm-specific protein. Multiple studies have characterized it as a testis-specific antigen ([Link](https://doi.org/10.1095/biolreprod61.5.1184)) and a novel, sperm-specific PKA-anchoring protein ([Link](https://doi.org/10.1210/mend.13.5.0278)). The gene's function is intimately tied to the unique architecture of spermatozoa. Gene Ontology annotations place the [AKAP3](/details-gene/10566) protein in the [sperm fibrous sheath](/details-go/GO:0035686), the major cytoskeletal structure of the flagellum, as well as the [sperm midpiece](/details-go/GO:0097225) and [sperm principal piece](/details-go/GO:0097228). This specific localization suggests that [AKAP3](/details-gene/10566) acts as a central organizing hub for signaling complexes that regulate the biomechanical functions of the sperm tail. Its presence is also noted in the [acrosomal vesicle](/details-go/GO:0001669), indicating an additional role in the events leading to fertilization. ## Pathways and Molecular Function The molecular function of [AKAP3](/details-gene/10566) is centered on its ability to act as a scaffold, primarily through its [protein kinase a binding](/details-go/GO:0051018) activity. By anchoring PKA, it ensures that downstream phosphorylation events occur at the right place and time within the spermatozoon, which is critical for a number of biological processes. This scaffolding function is essential for: * **Sperm Motility:** [AKAP3](/details-gene/10566) is integral to [flagellated sperm motility](/details-go/GO:0030317). PKA signaling is a known regulator of dynein motor activity within the flagellum, and the precise localization of PKA by [AKAP3](/details-gene/10566) is thought to be necessary for the coordinated phosphorylation of proteins that drive flagellar beating. Studies have shown it undergoes tyrosine phosphorylation during sperm capacitation, a process required for motility and fertilization ([Link](https://doi.org/10.1074/jbc.m202325200)). * **Fertilization:** The protein is involved in the [acrosome reaction](/details-go/GO:0007340), a crucial step where the sperm releases enzymes to penetrate the egg's outer layer. This suggests [AKAP3](/details-gene/10566)-mediated signaling in the sperm head is required for successful fertilization. Early work also suggested its involvement in oocyte recognition ([Link](https://doi.org/10.1006/bbrc.1999.0728)). * **Protein Localization:** More broadly, it contributes to the [establishment of protein localization](/details-go/GO:0045184), a function consistent with its role as a structural and signaling hub within the highly organized sperm cell. ## Research Directions The established link between [AKAP3](/details-gene/10566) mutations and male infertility provides a clear path for further investigation into the molecular mechanisms of sperm dysfunction. **Proposed Hypotheses:** 1. Specific missense mutations within the PKA-binding domain of [AKAP3](/details-gene/10566) selectively abrogate PKA anchoring, leading to impaired flagellar motility and asthenozoospermia, while other mutations in structural domains of the protein may lead to more severe flagellar assembly defects (multiple morphological abnormalities of the sperm flagella). 2. The role of [AKAP3](/details-gene/10566) in the [acrosome reaction](/details-go/GO:0007340) is dependent on its phosphorylation status during capacitation. Disruption of these phosphorylation sites may prevent the localized PKA signaling necessary to initiate acrosomal exocytosis, leading to fertilization failure even in motile sperm. **Experimental Approach:** To test the first hypothesis, a powerful approach would be to use a murine model. A knock-in mouse model could be generated using CRISPR-Cas9 to introduce a specific, patient-derived missense mutation into the PKA-binding domain of the mouse *Akap3* gene. Spermatozoa from homozygous mutant mice would be compared to wild-type controls. Key experiments would include: (1) Computer-assisted sperm analysis (CASA) to quantitatively assess motility parameters like velocity and beat frequency. (2) Co-immunoprecipitation assays using sperm lysates to determine if the mutation disrupts the physical interaction between AKAP3 and PKA regulatory subunits. (3) Proximity ligation assays (PLA) on fixed spermatozoa to visualize the subcellular co-localization of AKAP3 and PKA in situ, confirming whether the mutation displaces PKA from the fibrous sheath. **Therapeutic Potential:** As a structural protein whose loss-of-function leads to disease, [AKAP3](/details-gene/10566) is not a conventional therapeutic target for inhibition or activation. Its primary clinical value lies in diagnostics. Mutations in [AKAP3](/details-gene/10566) are a definitive cause of monogenic male infertility ([Link](https://doi.org/10.1136/jmedgenet-2021-108271)). Therefore, incorporating [AKAP3](/details-gene/10566) into genetic screening panels for men with idiopathic infertility, particularly those presenting with asthenoteratozoospermia, could provide a precise molecular diagnosis. This information would be invaluable for genetic counseling and for guiding couples towards the most appropriate assisted reproductive technologies, such as intracytoplasmic sperm injection (ICSI).

Genular Protein ID: 3755103955

Symbol: AKAP3_HUMAN

Name: A-kinase anchor protein 3

UniProtKB Accession Codes:

O75969 O75945 Q86X01 Q9UM61

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 2 ExpressionAtlas 1 GO 14 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 6 SIGNOR 1 SMART 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10334916

Title: Cloning and characterization of SOB1, a new testis-specific cDNA encoding a human sperm protein probably involved in oocyte recognition.

PubMed ID: 10334916

DOI: 10.1006/bbrc.1999.0728

PubMed ID: 10529264

Title: FSP95, a testis-specific 95-kilodalton fibrous sheath antigen that undergoes tyrosine phosphorylation in capacitated human spermatozoa.

PubMed ID: 10529264

DOI: 10.1095/biolreprod61.5.1184

PubMed ID: 10319321

Title: Isolation and molecular characterization of AKAP110, a novel, sperm-specific protein kinase A-anchoring protein.

PubMed ID: 10319321

DOI: 10.1210/mend.13.5.0278

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11278869

Title: Identification of sperm-specific proteins that interact with A-kinase anchoring proteins in a manner similar to the type II regulatory subunit of PKA.

PubMed ID: 11278869

DOI: 10.1074/jbc.m011252200

PubMed ID: 12509440

Title: Phosphoproteome analysis of capacitated human sperm. Evidence of tyrosine phosphorylation of a kinase-anchoring protein 3 and valosin-containing protein/p97 during capacitation.

PubMed ID: 12509440

DOI: 10.1074/jbc.m202325200

PubMed ID: 30683861

Title: Loss-of-function mutations in QRICH2 cause male infertility with multiple morphological abnormalities of the sperm flagella.

PubMed ID: 30683861

DOI: 10.1038/s41467-018-08182-x

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

PubMed ID: 35228300

Title: Homozygous variants in AKAP3 induce asthenoteratozoospermia and male infertility.

PubMed ID: 35228300

DOI: 10.1136/jmedgenet-2021-108271

Sequence Information:

  • Length: 853
  • Mass: 94751
  • Checksum: CFDEA26922B5A86E
  • Sequence:
    • MSEKVDWLQS QNGVCKVDVY SPGDNQAQDW KMDTSTDPVR VLSWLRRDLE KSTAEFQDVR 
FKPGESFGGE TSNSGDPHKG FSVDYYNTTT KGTPERLHFE MTHKEIPCQG PRAQLGNGSS 
VDEVSFYANR LTNLVIAMAR KEINEKIDGS ENKCVYQSLY MGNEPTPTKS LSKIASELVN 
ETVSACSRNA APDKAPGSGD RVSGSSQSPP NLKYKSTLKI KESTKERQGP DDKPPSKKSF 
FYKEVFESRN GDYAREGGRF FPRERKRFRG QERPDDFTAS VSEGIMTYAN SVVSDMMVSI 
MKTLKIQVKD TTIATILLKK VLLKHAKEVV SDLIDSFLRN LHSVTGTLMT DTQFVSAVKR 
TVFSHGSQKA TDIMDAMLRK LYNVMFAKKV PEHVRKAQDK AESYSLISMK GMGDPKNRNV 
NFAMKSETKL REKMYSEPKS EEETCAKTLG EHIIKEGLTL WHKTQQKECK SLGFQHAAFE 
APNTQRKPAS DISFEYPEDI GNLSLPPYPP EKPENFMYDS DSWAEDLIVS ALLLIQYHLA 
QGGRRDARSF VEAAGTTNFP ANEPPVAPDE SCLKSAPIVG DQEQAEKKDL RSVFFNFIRN 
LLSETIFKRD QSPEPKVPEQ PVKEDRKLCE RPLASSPPRL YEDDETPGAL SGLTKMAVSQ 
IDGHMSGQMV EHLMNSVMKL CVIIAKSCDA SLAELGDDKS GDASRLTSAF PDSLYECLPA 
KGTGSAEAVL QNAYQAIHNE MRGTSGQPPE GCAAPTVIVS NHNLTDTVQN KQLQAVLQWV 
AASELNVPIL YFAGDDEGIQ EKLLQLSAAA VDKGCSVGEV LQSVLRYEKE RQLNEAVGNV 
TPLQLLDWLM VNL