Ku protein: Difference between revisions

<StructureSection load='1JEY' size='475' side='right' caption='Structure of the Ku heterodimer bound to DNA (PDB entry [[1JEY]])' scene=''>

== Overview ==

The <scene name='56/567269/Ku_heterodimer/3'>Ku heterodimer</scene> (<scene name='56/567269/Ku70_subunit/3'>Ku70</scene> and <scene name='56/567269/Ku80_subunit/3'>Ku80</scene> subunits) contributes to genomic integrity through its ability to bind DNA double-strand breaks and facilitate repair by the non-homologous end-joining pathway. The crystal structure of the human Ku heterodimer was determined both alone and bound to a 55-nucleotide <scene name='56/567269/Bound_dna/3'>DNA</scene> element at 2.7 and 2.5 A resolution, respectively. Ku70 and Ku80 share a common topology and form a dyad-symmetrical molecule with a preformed ring that encircles duplex DNA. The binding site can cradle two full turns of DNA while encircling only the central 3-4 base pairs (bp). Ku makes no contacts with DNA bases and few with the sugar-phosphate backbone, but it fits sterically to major and minor groove contours so as to position the DNA helix in a defined path through the protein ring. These features seem well designed to structurally support broken DNA ends and to bring the DNA helix into phase across the junction during end processing and ligation. <ref> PMID: 11493912</ref>

</StructureSection>

== Structure ==

The <scene name='56/567269/Ku_ring/1'>Ku Ring</scene> is composed of a broad base of beta barrels that cradle the DNA, and a narrow bridge that serves to protect the double strand break from base pairing with other DNA base pairs and degradation <ref> PMID: 11493912</ref>.  There is little interaction between the ring and the backbone or base pairs of DNA; instead, the ring associates with DNA by the cradle fitting into the major grooves of the helix <ref> PMID: 11493912</ref>.  The positive electrostatic charge caused by polarization of the ring also allows the negatively charged backbone of DNA to be guided into the correct position <ref> PMID: 11493912</ref> (NEED SCENE OF POS CHARGE OR POLARIZATION).  The Ku protein also has a high affinity to DNA due to its form being preset for the helix. As a result of the asymmetric ring, there is a strong preference (Kd value of 1.5 to 4 X 10^-10 M<ref> PMID: 11493912</ref>) for the <scene name='56/567269/Ku_ring/1'>Ku Ring</scene> to slide onto the ends of DNA <ref> PMID: 11493912</ref>.  In addition, other asymmetric features, such as a abundance of Asp residues on the N terminus of the <scene name='56/567269/Ku_heterodimer/3'>Ku heterodimer</scene> (NEED SCENE OF ASP ON N-TERMINUS OR MAYBE JUST ASP IN GENERAL),  prevent the Ku protein from sliding further on the DNA helix.  While wrapping over the entire helix, the <scene name='56/567269/Ku_ring/1'>Ku Ring</scene> is thin over the bridge, allowing ligases and polymerases to efficiently interact in [[non-homologous end joining (NHEJ)]]. <ref> PMID: 11493912</ref>  

<scene name='56/567269/Ku70_subunit/3'>Ku70/80 subunits</scene>

Consisting of three domains (<scene name='56/567269/Ku70_dimer/2'>α/β-Domain</scene>, <scene name='56/567269/Ku70_dimer/4'>β-barrel</scene>, <scene name='56/567269/Ku70_dimer/7'>C-terminal arm</scene>), the <scene name='56/567269/Ku70_subunit/3'>Ku70 subunit</scene>  dimerizes with the <scene name='56/567269/Ku80_subunit/3'>Ku80 subunit</scene> to form the protein <ref> PMID: 11493912</ref>.  Unlike other DNA binding proteins, the Ku protein is asymmetrical from the differences between the Ku70 and Ku80 subunits.  This asymmetry leads to different favorable locations for DNA based on major and minor grooves <ref> PMID: 11493912</ref>.  The <scene name='56/567269/Ku70_subunit/3'>Ku70 subunit</scene> is angled closer to <scene name='56/567269/Bound_dna/3'>DNA</scene> at the double strand break, providing protectiion and interaction with its domains (SOURCE #2).  In contrast, the <scene name='56/567269/Ku80_subunit/3'>Ku80 subunit</scene> associates with <scene name='56/567269/Bound_dna/3'>DNA</scene> away from the free end <ref> PMID: 11493912</ref>.  Once a homodimer, the protein has diverged into two domains that are now 15% similar in residues (SOURCE #3).

<scene name='56/567269/Ku70_dimer/2'>α/β-Domain</scene>

Contained inside the <scene name='56/567269/Ku70_dimer/2'>α/β-Domain</scene> is a [[Rossman fold]] at the N terminus that is used to bind nucleotides in <scene name='56/567269/Bound_dna/3'>DNA</scene> <ref> PMID: 11493912</ref>. In terms of protein structure, the <scene name='56/567269/Ku70_dimer/2'>α/β-Domain</scene> contributes little to the dimer interface between the subunits.  The C terminus of the domain can be bound to other repair molecules, using <scene name='56/567269/Ku70_dimer/2'>α/β-Domain</scene> as a scaffold <ref> PMID: 11493912</ref>.

<scene name='56/567269/Ku70_dimer/4'>β-barrel</scene>

The <scene name='56/567269/Ku70_dimer/4'>β-barrel</scene> is the main source of interactions of the <scene name='56/567269/Ku_heterodimer/3'>Ku heterodimer</scene> itself and <scene name='56/567269/Bound_dna/3'>DNA helix</scene>, with each <scene name='56/567269/Ku70_dimer/4'>β-barrel</scene> being composed of seven β strands with the majority in antiparallel arrangement <ref> PMID: 11493912</ref>. The quantity of the strands lends the structures to be symmetrical.  Both <scene name='56/567269/Ku70_dimer/4'>β-barrels</scene> in the dimer form the base of the cradle by fitting in the grooves of <scene name='56/567269/Bound_dna/3'>DNA</scene>.

<scene name='56/567269/Ku70_dimer/7'>C-terminal arm</scene>

The <scene name='56/567269/Ku70_dimer/7'>C-terminal arm</scene> is an α-helical domain that associates with the β-barrel of the opposite subunit, with the arm stretching across the <scene name='56/567269/Bound_dna/3'>DNA helix</scene> <ref> PMID: 11493912</ref>.  As a result, the <scene name='56/567269/Ku70_dimer/7'>C-terminal arm</scene> strengthens the cradle composed of the two β-barrels.   

<scene name='56/567269/Ku70_dimer/6'>DNA binding ring</scene>

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