User:Patrick Wiencek/AHNAK

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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

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

Obesity

Aging

Evolutionarily Related Proteins

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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