FC0057
Telomere-binding protein subunit β  -  DNA

Biological function
Telomere nucleoprotein complexes serve critical functions in eukaryotic cells, protecting the ends of chromosomes from degradation, recombination, and end-to-end fusion events.

Domain organization/sequence features
In S. nova the single-stranded DNA forms a tenacious salt-resistant complex with two protein subunits, a 56-kDa protein called α and a 41-kDa protein called β. The α protein contains two structurally and functionally separable domains. The 41-kDa β protein is readily processed by proteolysis to yield a 28-kDa C-terminally truncated form, β 28-kDa, that retains many of the single- stranded DNA-binding properties of full-length. The lysine-rich, protease-sensitive, C-terminal portion of β is unstructured and contains sites for phosphorylation that may be important for regulation of αβ DNA complex disassembly.

Structural evidence
Comparison of the full-length αβDNA co-crystal structure with the protease-resistant core domain of β showed that the protein- DNA interface is extremely well preserved. No additional electron density was apparent, confirming that the C-terminal tail of β is unstructured. The flexible and positively charged C-terminal tail may become somewhat more solvent-exposed when β associates with the telomere complex. The lysine-rich C-terminal tail of β may be critical for regulation of telomere complex stability and higher order organization of chromosomes within the nucleus.

Biochemical evidence
α and β telomere proteins bind cooperatively with single-stranded DNA to form a ternary αβ DNA complex. Association of telomere protein subunits is DNA-dependent, and α−β association enhances DNA affinity. ITC measurements show that a significant portion of binding energy and heat capacity could be assigned to structural reorganization involving protein-protein interactions and repositioning of the DNA. Structural reorganization probably represents the driving force behind an allosteric switch that modulates DNA binding affinity and, importantly, DNA position.

Structure/Mechanism
Consistent with a relatively unstable αβ complex, initial α-β association does not result in a fully formed protein-protein interface. The structural changes required for a complete protein-protein interface only occur when DNA is added to the system. In addition to augmenting telomere complex stability, β association is coupled with repositioning of the DNA with respect to α, which may be an important step in activation of telomerase.

Mechanism category
tethering

Posttranslational modification
Regulation of telomere complex dissociation involves post-translational modifications in the lysine-rich C-terminal portion of β. Although the C-terminal tail of β appears dispensable for single-stranded telomere DNA binding, phosphorylation of β in this region may nevertheless be a crucial requirement for complex disassembly. In one possible mechanism, phosphorylation could inhibit association of β with the αDNA complex, as suggested by in vitro experiments. In the cell, modification of β may also facilitate interaction with other nuclear components required for DNA dissociation. These nuclear components could trigger complex disassembly by making use of the allosteric switch built into the αβDNA complex. Since structural reorganization intimately links α−β interactions with DNA-protein stability, accessory proteins recruited to the telomere through interaction with β could weaken the αβDNA complex and provide a route for DNA dissociation simply by weakening α −β interactions.

Significance
The fuzzy region and its post-translational modifications provide an allosteric switch for DNA binding and dissociation.