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Introduction
AHNAK is a protein characterized by its large size (700 kDa) and its unique tripartite structure. Originally identified in 1989 as a desmosomal plaque protein purified from bovine muzzle epidermis called desmoyokin, AHNAK is now recognized as a scaffolding protein that has implicated in a wide range of diverse biological processes. This includes processes from Ca2+ channel regulation and cell adhesion to cell cycle arrest. Despite the diversity of processes that AHNAK is involved in, they’re unified in the formation of multi-protein complexes, AHNAK likely serving as a scaffolding protein for other proteins in the complex.
In alignment with AHNAK’s many functions, AHNAK has several identified subcellular localizations depending on cell type, intercellular contacts, and the phosphorylation state of the protein. These include the plasma membrane, the cytoplasm and the nucleus. There is also evidence supporting AHNAK’s export to the extracellular space.
Structure
AHNAK has a unique structure made up of three main domains: the N-terminal domain, the central repeated domain, and the C-terminal domain (Figure 1). These domains are 251, 4300, and 1002 amino acids in length, respectively.
The Central Repeated Domain
The central repeated domain is comprised of many 128 amino acid repeated elements, these generally being rich in charged residues. These elements are highly conserved, on average sharing an identity of 80% and maintaining both polarity and charge in their amino acid substitutions. Underlying the 128-residue repeat is a 7-residue repeat with the pattern: Φ+ΦP+Φ+, where Φ are hydrophobic residues, + are charged residues, and P is a proline residue. A molecular model of the structure resembles that of a β-strand, where intermolecular hydrogen bonding could cause the protein to adopt a seven or eight-stranded barrel structure with a diameter of 9.8 or 10.1 Å, respectively. This results in an polyionic rod structure as long as 1.2 µm.
Protein Interactions and Post-Translational Modifications
AHNAK contains many different sites for protein-protein interactions and post-translational modifications (Figure 1). The UniProt entry for human AHNAK (Q09666) shows 179 sites of post-translational modification distributed across all 3 of AHNAK’s domains. The N-terminal domain of AHNAK contains a PDZ domain. PDZ domains are domains involved in protein interaction, typically recognizing short C-terminal amino acid sequences of their target proteins. AHNAK has been demonstrated undergoing heterodimerization between its large and small isoforms, likely through interactions with their PDZ domains. The small AHNAK isoform is also capable of homodimerization.
Function
AHNAK in Disease
Despite initial mouse models that showed no phenotypic defects in AHNAK-null mice, AHNAK has been related to several different diseases. These include but are not limited to: cancer, obesity, and aging.
Cancer
AHNAK’s roles in cancer and tumor metastasis have recently become a large part of the research being done with AHNAK. Due to AHNAK’s implications in many different biological processes, AHNAK seems to promote cancer in some contexts and serve as a tumor suppressor in others. Due to its functionality in cytoskeletal stabilization and interaction with actin filaments, AHNAK was found to be essential in actin-rich pseudopod protrusion across several different metastatic human tumor cell lines. AHNAK knockdown caused these cells to retract their pseudopods and reverse the epithelial to mesenchymal transition that is necessary for cancer metastasis. Similarly, significantly higher levels of AHNAK expression were detected in mesotheliomal cell lines, and migration and invasion were both decreased following AHNAK knockdown.
AHNAK can also act as a tumor suppressor because of its role in the TFGβ/Smad pathway. Overexpression of AHNAK in mouse fibroblast cell resulted in increased cell-cycle arrest. Analysis of AHNAK mRNA levels in glioma demonstrated that AHNAK was down-regulated in some cell lines, and was a statistically significant prognostic factor for poor survival of glioma patients. Similar results were shown in a study of AHNAK in triple-negative breast cancer, also associating AHNAK with the AMK/MAPK signaling pathway and the Wnt/β-catenin pathway. These differing effects of AHNAK in cancer may involve its regulation via TGFβ, which has both tumor suppressor and tumor promotor roles.
Obesity
In a 2010 study, AHNAK knock out mice were found to have a resistance to high-fat diet-induced obesity. The authors indicated that the mechanism of resistance likely was related to changes in amino acid levels related to fat metabolism, but did not elucidate a direct mechanism for the effect that they saw. Similarly, impaired adipogenesis has been observed in AHNAK null mice. Adipocyte differentiation and adipogenesis relies on the expression of Pparγ2, which in turn relies on Smad signaling. By potentiating Pparγ2 signaling, AHNAK serves as a regulator of metabolic homeostasis and might be useful in future metabolic disorder studies related to obesity.
Aging
AHNAK has also been implicated in the aging process. In an analysis of gene expression analysis of human skeletal muscle biopsies, AHNAK displayed increased expression with increased age. Similarly, in an analysis of gene expression profiles of multiple male age groups, high AHNAK expression levels were correlated with low maximal oxygen uptake and poor muscle fitness.
Evolutionarily Related Proteins
AHNAK is ubiquitously expressed in most tissues throughout the body, and the AHNAK family of proteins is specific to vertebrates. There are 3 AHNAK-like genes, AHNAK1, AHNAK2, and Periaxin. AHNAK2 is a 600-kDa protein that is hypothesized to have a similar localization and function to AHNAK. Periaxin is a 155-kDa protein that is important in the myelination of the peripheral nervous system.
All 3 of these proteins have similar genetic structure (several small exons that are upstream of a single large exon), tripartite repeat protein structure, and conserved N-terminal PDZ domain. Both AHNAK and Periaxin have large and small isoforms. Phylogenetic analysis of both the PDZ domains and the whole sequences of the 3 AHNAK family members and their isoforms indicates that the AHNAK protein family is derived from a common ancestor and that Periaxin and AHNAK2 are more similar than AHNAK.
AHNAK has previously been reported dimerizing, and the PDZ domains of AHNAK2 and Periaxin have been crystallized as homodimers (sources of AHNAK dimer and PDZ dimerization). This dimerization may be an important piece of the scaffolding functions of the proteins in the AHNAK family.
Links to Available AHNAK Structures
AHNAK Structures
- 4ftg - An AHNAK peptide in complex with the S1—S1-/AnxA2 heterotetramer
- 4drw - The ternary complex between S1—A1-, an Annexin A2 N-terminal peptide and an AHNAK peptide
- 4hrg - p11-Annexin A2(N-terminal) Fusion protein complexed with AHNAK1 peptide
AHNAK Homolog Structures
- 4cn0 - An intertwined homodimer of the PDZ homology domain of AHNAK2
- 4cmz - An intertwined homodimer of the PDZ homology domain of periaxin
Structural highlights
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