Exon 10 encodes a microtubule binding repeat in the C-terminus in addition to three microtubule binding repeats existing in all tau isoforms.
Exon 10 (encodescodes the second of four imperfect 31 32 amino-acid microtubule-binding repeats in the C-terminal half of the protein.
GgLRP2 shows all of the hallmark structural elements and the domain organization typical of this endocytic receptor, including three (FX NPXY internalization motifs in the 213-residue cytoplasmic domain and four clusters of ligand-binding repeats in the large extracellular portion (Saito et al., 1994).
Concentrating on the known protein products within human brain (of which six are recognized), cassette splicing of exons 2 and 3 (E2 and E3), give rise to tau isoforms with 0, 1 or 2 amino-terminal repeats (0N-, 1N- or 2N-tau) and alternative splicing of exon 10 (E10), give isoforms with 3- or 4-microtubule-binding repeats in the carboxy-terminal half of tau (3R- or 4R-tau) (10).
The avian receptor was subsequently named LR8 (LR with 8 ligand binding repeats) in order to distinguish it from mammalian "VLDL receptors" that had been reported to bind VLDL (Takahashi et al., 1992).
The expression of four instead of three microtubule binding repeats results in tau-isoforms that differ in affinity to microtubules [8].
Of particular significance, exon 10 (encodescodes the second of four microtubule-binding repeated motifs in the C-terminal part of the protein.
Neurensin-1 (or Neuro-p24) is a lysosomal membrane protein that is enriched in neurons, specifically in neuritic processes, and has a cytosolic tail that contains a microtubule-binding domain homologous to binding repeats found in tau (199).
To investigate HNF4α binding to Alu repeats in the promoters of HNF4α target genes in vivo, we performed a ChIP assay for HNF4α in human hepatocellular carcinoma HepG2 cells that express HNF4α and many of its target genes.
The localization of methylated residues within the microtubule binding repeat region in proximity to the PHF6 and PHF6* nucleation centers makes Lys methylation a candidate modification for directly affecting normal tau interactions with binding partners such as microtubules as well as abnormal interactions such as aggregation and PHF formation.
All told there were nearly ~1.2 million HNF4α binding sites in Alu repeats in the human genome.
