The protein KIAA0564, also known as Von Willebrand Domain-containing Protein 8 (VWA8), was initially identified through the Kazusa cDNA project . The function of VWA8 was largely unknown, which prompted research into its tissue distribution, cellular location, and function .
Sequence analysis indicates that VWA8 contains a mitochondrial targeting sequence and domains responsible for ATPase activity . Human and mouse VWA8 have two isoforms: VWA8a and VWA8b. VWA8a consists of 1905 amino acids in both human and mouse, while VWA8b consists of 1039 and 1308 amino acids in human and mouse, respectively . The long and short isoforms in human and mouse share an identical amino acid sequence in the first 1039 (human) or 1038 (mouse) amino acids . The shorter isoforms lack the remaining amino acids due to extensions in Exon 26 that introduce a stop codon (TAA) in both species .
VWA8 has an AAA (ATPase) domain in the N-terminus, which includes Walker A and Walker B motifs . The Walker A motif (GXXGXGK[S/T]) forms a loop that binds to the alpha and beta phosphate moieties of the bound nucleotide, while the Walker B motif, which contains 4 aliphatic residues followed by 2 negatively charged residues, is important for interacting with $$Mg^{2+}$$ . Deletion of either the Walker A or Walker B motif largely blocked ATPase activity, which suggests that these motifs are essential for VWA8's ATPase activity .
Homology modeling, using the Phyre2 server, revealed that 52% of the VWA8a sequence could be modeled with 100% confidence based on the structure of the cytoplasmic dynein heavy chain (PDB c3ykhB) . VWA8a and the dynein heavy chain motor domain have 16% identity at the amino acid level . Furthermore, 90% of the VWA8b sequence could be modeled with 100% confidence using the cytoplasmic dynein heavy chain (c3vkhb) as a template . These models indicate structural similarities to dynein-related motor proteins .
| Protein | Template Protein | Percentage of Sequence Modeled | Confidence | Amino Acid Identity |
|---|---|---|---|---|
| VWA8a | Cytoplasmic dynein heavy chain | 52% | 100% | 16% |
| VWA8b | Cytoplasmic dynein heavy chain | 90% | 100% | N/A |