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===C-terminal CH domain=== | ===C-terminal CH domain=== | ||
The calponin-homology (CH) domains are helical structural units around 100 amino acids long. They comprise at least four helices, three of them forming a helical bundle. CH domains usually comprise elements of big multidomain proteins and are present either in singlet<ref>PMID: 19459066</ref> or duplex/tandem arrangement.<ref>PMID: 19565353</ref> The tandem arrangement of CH domains is often associated with F-actin binding<ref>PMID: 9708889</ref><ref>PMID: 18952167</ref> (and is thus called actin-binding domain or ABD), but generally CH domains seem to be characterized by functional plasticity and ability to bind various structural motifs.<ref>PMID: 11911887</ref> In the case of alpha-parvin, the interactions of CH domains with both F-actin and other partners (paxillin, ILK) are observed. The interactions with paxillin and ILK are mediated by a single CH domain, the C-terminal one. This domain has attracted most attention. While no full-length structure of alpha-parvin has been solved to date, the structure of the C-terminal CH domain, on its own<ref>PMID: 18940607</ref> and in complexes (with paxillin<ref>PMID: 18940607</ref><ref>PMID: 18508764</ref> and the pseudokinase domain of ILK<ref>PMID: 20005845</ref>) are available. | The calponin-homology (CH) domains are helical structural units around 100 amino acids long. They comprise at least four helices, three of them forming a helical bundle. CH domains usually comprise elements of big multidomain proteins and are present either in singlet<ref>PMID: 19459066</ref> or duplex/tandem arrangement.<ref>PMID: 19565353</ref> The tandem arrangement of CH domains is often associated with F-actin binding<ref>PMID: 9708889</ref><ref>PMID: 18952167</ref> (and is thus called actin-binding domain or ABD), but generally CH domains seem to be characterized by functional plasticity and ability to bind various structural motifs.<ref>PMID: 11911887</ref> In the case of alpha-parvin, the interactions of CH domains with both F-actin and other partners (paxillin, ILK) are observed. The interactions with paxillin and ILK are mediated by a single CH domain, the C-terminal one. This domain has attracted most attention. While no full-length structure of alpha-parvin has been solved to date, the structure of the C-terminal CH domain, on its own<ref>PMID: 18940607</ref> and in complexes (with paxillin<ref>PMID: 18940607</ref><ref>PMID: 18508764</ref> and the pseudokinase domain of ILK<ref>PMID: 20005845</ref>) are available. | ||
[[Image:Consurf_key_small.gif|right|200px]][[2vzc]] shows the structure of the <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin/1'>C-terminal CH domain of alpha-parvin</scene> at around 1.05 Å. When a sequence alignment of alpha-parvin with all its sequence homologues is performed and the protein is coloured according to <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin/3'>the degree of sequence conservation</scene>, one can see that the highest degree of conservation is exhibited by the residues located in <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin/5'>the core helices</scene>, while the residues in linker helices and loops are less conserved. When the <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/1'>structural superposition</scene> of the <font color='brown'>C-terminal CH domain of alpha-parvin</font> and <font color='DimGrey'>one of the CH domains of alpha-actinin 3</font> ([[1wku]]) is performed, a good overall overlap is observed, as represented by the RMSD of 1.19 Å for 103 equivalent C<sup>α</sup> positions, despite low sequence homology (≤26% identity).<ref>PMID: 18940607</ref> Again the best overlap is seen for the core helices. This suggests that the structural framework of CH domain and its core in particular is quite robust throughout evolution. The most diverged fragments in the C-terminal CH domain of alpha-parvin correspond to 1) an <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/3'>additional helix</scene> (so called N-terminal linker helix) located at the N-terminal end of the domain and not observed in any other CH domain and 2) a <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/5'>long loop</scene> between two helices. One could ask whether the N-terminal linker helix is an integral part of the C-terminal CH domain or just a part of a linker region between the two CH domains. The fact that it interacts strongly with the core helices by means of both electrostatic (<scene name='Alpha-parvin/Parvin_overlap/1'>residues D248, D251 and D255 with K355 and R359</scene>) and hydrophobic (<scene name='Alpha-parvin/Parvin_overlap/4'>residues F250, L253 and F254 with L354, K355, L358, R359, K260 and L261</scene>) interactions suggests that it is indeed integral to the domain. The long loop mentioned above contains a <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/6'>3-amino acid insertion</scene> (313-315) relative to other known CH domains and differs in conformation between different structures of alpha-parvin, suggesting it is relatively flexible. | [[Image:Consurf_key_small.gif|right|200px]][[2vzc]] shows the structure of the <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin/1'>C-terminal CH domain of alpha-parvin</scene> at around 1.05 Å. When a sequence alignment of alpha-parvin with all its sequence homologues is performed and the protein is coloured according to <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin/3'>the degree of sequence conservation</scene>, one can see that the highest degree of conservation is exhibited by the residues located in <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin/5'>the core helices</scene>, while the residues in linker helices and loops are less conserved. When the <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/1'>structural superposition</scene> of the <font color='brown'>C-terminal CH domain of alpha-parvin</font> and <font color='DimGrey'>one of the CH domains of alpha-actinin 3</font> ([[1wku]]) is performed, a good overall overlap is observed, as represented by the RMSD of 1.19 Å for 103 equivalent C<sup>α</sup> positions, despite low sequence homology (≤26% identity).<ref>PMID: 18940607</ref> Again the best overlap is seen for the core helices. This suggests that the structural framework of CH domain and its core in particular is quite robust throughout evolution. The most diverged fragments in the C-terminal CH domain of alpha-parvin correspond to 1) an <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/3'>additional helix</scene> (so called N-terminal linker helix) located at the N-terminal end of the domain and not observed in any other CH domain and 2) a <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/5'>long loop</scene> between two helices. One could ask whether the N-terminal linker helix is an integral part of the C-terminal CH domain or just a part of a linker region between the two CH domains. The fact that it interacts strongly with the core helices by means of both electrostatic (<scene name='Alpha-parvin/Parvin_overlap/1'>residues D248, D251 and D255 with K355 and R359</scene>) and hydrophobic (<scene name='Alpha-parvin/Parvin_overlap/4'>residues F250, L253 and F254 with L354, K355, L358, R359, K260 and L261</scene>) interactions suggests that it is indeed integral to the domain. The long loop mentioned above contains a <scene name='User:Marcin_Jozef_Suskiewicz/Sandbox_Parvin//Parvin_overlap/6'>3-amino acid insertion</scene> (313-315) relative to other known CH domains and differs in conformation between different structures of alpha-parvin, suggesting it is relatively flexible.<ref>PMID: 18940607</ref> | ||
===Paxillin binding=== | ===Paxillin binding=== | ||
<Structure load='Complex_parvin.pdb' size='360' scene='Alpha-parvin/Parvin/2' frame='true' align='right' caption='C-terminal CH domain of alpha-parvin bound to paxillin LD motif'/> | <Structure load='Complex_parvin.pdb' size='360' scene='Alpha-parvin/Parvin/2' frame='true' align='right' caption='C-terminal CH domain of alpha-parvin bound to paxillin LD motif'/> | ||
The <scene name='Alpha-parvin/Parvin/2'>scene on the right</scene> shows the superimposition of three structures of alpha-parvin bound to paxillin LD motifs, LD1 ([[2vzd]]), LD2 ([2vzg]] and LD4 ([[2vzi]]) respectively. These three LD motifs differ in sequence, but they are all helical. Surprisingly, the orientation of LD1 binding is reversed compared to that of LD2 and LD4. One of the LD motifs (LD1) is shown in the scene, represented by a blue helix. LD2 and LD4 bind in the same location. As you can see, all three peptides, despite different sequences and different binding orientations, induce a very similar conformation of alpha-parvin, as represented by a very good alignment of the three structures. In particular, residues 248 to 264, which experience conformational change upon binding, are similar in all complexes with RMSD values of 0.28 Å (LD1 versus LD2), 0.23 Å (LD1 versus LD4), and 0.15 Å (LD2 versus LD4) in 16 equivalent C<sup>α</sup> positions. | The <scene name='Alpha-parvin/Parvin/2'>scene on the right</scene> shows the superimposition of three structures of alpha-parvin bound to paxillin LD motifs, LD1 ([[2vzd]]), LD2 ([2vzg]] and LD4 ([[2vzi]]) respectively. These three LD motifs differ in sequence, but they are all helical. Surprisingly, the orientation of LD1 binding is reversed compared to that of LD2 and LD4. One of the LD motifs (LD1) is shown in the scene, represented by a blue helix. LD2 and LD4 bind in the same location. As you can see, all three peptides, despite different sequences and different binding orientations, induce a very similar conformation of alpha-parvin, as represented by a very good alignment of the three structures coloured differently. In particular, residues 248 to 264, which experience conformational change upon binding, are similar in all complexes with RMSD values of 0.28 Å (LD1 versus LD2), 0.23 Å (LD1 versus LD4), and 0.15 Å (LD2 versus LD4) in 16 equivalent C<sup>α</sup> positions.<ref>PMID: 18940607</ref> | ||
==References== | ==References== | ||
<references /> | <references /> | ||