Teneurins are type II transmembrane proteins expressed during pattern formation and neurogenesis with an intracellular domain that can be transported to the nucleus and an extracellular domain that can be shed into the extracellular milieu. In Drosophila melanogaster, Caenorhabditis elegans, and mouse the knockdown or knockout of teneurin expression can lead to abnormal patterning, defasciculation, and abnormal pathfinding of neurites, and the disruption of basement membranes. Here, we have identified and analyzed teneurins from a broad range of metazoan genomes for nuclear localization sequences, protein interaction domains, and furin cleavage sites and have cloned and sequenced the intracellular domains of human and avian teneurins to analyze alternative splicing. The basic organization of teneurins is highly conserved in Bilateria: all teneurins have epidermal growth factor (EGF) repeats, a cysteine-rich domain, and a large region identical in organization to the carboxy-half of prokaryotic YD-repeat proteins. Teneurins were not found in the genomes of sponges, cnidarians, or placozoa, but the choanoflagellate Monosiga brevicollis has a gene encoding a predicted teneurin with a transmembrane domain, EGF repeats, a cysteine-rich domain, and a region homologous to YD-repeat proteins. Further examination revealed that most of the extracellular domain of the M. brevicollis teneurin is encoded on a single huge 6,829-bp exon and that the cysteine-rich domain is similar to sequences found in an enzyme expressed by the diatom Phaeodactylum tricornutum. This leads us to suggest that teneurins are complex hybrid fusion proteins that evolved in a choanoflagellate via horizontal gene transfer from both a prokaryotic gene and a diatom or algal gene, perhaps to improve the capacity of the choanoflagellate to bind to its prokaryotic prey. As choanoflagellates are considered to be the closest living relatives of animals, the expression of a primitive teneurin by an ancestral choanoflagellate may have facilitated the evolution of multicellularity and complex histogenesis in metazoa.
Aggregation of Tau into amyloid-like fibrils is a key process in neurodegenerative diseases such as Alzheimer. To understand how natively disordered Tau stabilizes conformations that favor pathological aggregation, we applied single-molecule force spectroscopy. Intramolecular interactions that fold polypeptide stretches of ϳ19 and ϳ42 amino acids in the functionally important repeat domain of full-length human Tau (hTau40) support aggregation. In contrast, the unstructured N terminus randomly folds long polypeptide stretches >100 amino acids that prevent aggregation. The pro-aggregant mutant hTau40⌬K280 observed in frontotemporal dementia favored the folding of short polypeptide stretches and suppressed the folding of long ones. This trend was reversed in the anti-aggregant mutant hTau40⌬K280/PP. The aggregation inducer heparin introduced strong interactions in hTau40 and hTau40⌬K280 that stabilized aggregation-prone conformations. We show that the conformation and aggregation of Tau are regulated through a complex balance of different intra-and intermolecular interactions.Amyloid forming proteins such as ␣-synuclein, the prion protein (1), and Tau (2) contain unstructured domains or belong to the family of natively unfolded or intrinsically disordered proteins (IDPs) 3 (3). The aggregation of Tau into amyloid-like fibers, known as paired helical filaments (4, 5), is a key process in human protein aggregation diseases that are summarized as tauopathies. In vivo, Tau binds and stabilizes microtubules (MTs) to regulate the cellular MT network. The dissociation of Tau from MTs is controlled by the phosphorylation of Tau at multiple sites (6, 7). The longest human Tau isoform, hTau40 (441 amino acids (aa)), contains a ϳ250-aa long N terminus of unknown function, whereas the C terminus comprises the Tau repeat domain, which encompasses four ϳ31-aa long semi-conserved repeats (R1 to R4) flanked by proline-rich stretches (Fig. 1A). Both, binding to MTs and fibril assembly are mediated through the Tau repeat domain (8, 9).As most IDPs, Tau shows a high content of charged aa residues and a low hydrophobicity, which result in an extended solution conformation with a large radius of gyration (10). In solution, Tau has no stable secondary and tertiary structure, as judged by CD and Fourier transform infrared spectroscopy (10). The Stokes radius of Tau increases upon chemical denaturation with urea or guanidine hydrochloride (11, 12) indicating some limited folding. NMR experiments revealed transient secondary structures in hTau40 that partially interact with other polypeptide regions (13). Two hexapeptide motifs, PHF6* in R2 and PHF6 in R3, can adopt -strand conformation and are predominantly responsible for Tau aggregation into fibrils (9, 14). Using Förster resonance energy transfer (11), the transient "paper clip"-like folding of the C and N termini onto the repeat domain was detected in hTau40. After removing the N-and C-terminal domains, the Tau repeat domain exhibits faster aggregation than full-length Tau (15). Th...
Background:The intracellular domain of teneurins translocates to the nucleus and is thought to influence transcription. Results: The teneurin-1 intracellular domain binds the transcriptional repressor HINT1 and induces MITF target genes. Conclusion:The teneurin-1 intracellular domain prevents HINT1 from repressing MITF at its target gene promoters. Significance: This is a novel mechanism for a teneurin-mediated transcriptional control.
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