Parvin: Difference between revisions

Alpha-parvin's structure can be divided into four regions: 1) N-terminal flexible domain (residues 1-96), 2) N-terminal CH domain (97-200 according to SMART<ref>PMID: 9600884</ref>), 3) linker region (201-241) and 4) C-terminal CH domain (242-372 identified by limited subtilisin proteolysis<ref>PMID: 18940607</ref>). Most interactions of alpha-parvin are mapped to the C-terminal CH domain, but CdGAP and perhaps alphaPIX or other, yet unknown partners, interact with the N-terminal flexibile domain. This flexible domain seems to lack a well defined 3D structure and can therefore be classified as a putative [[Intrinsically Disordered Protein|intrinsically disordered]] region. The interactions of this regions with the binding partners are therefore likely to be characterized by relatively low affinity, but high affinity nonetheless.<ref>PMID: 19265676</ref> The abovementioned phosphorylation sites (serines 4 and 8) involved in focal adhesion regulation are located in this segment, which makes them so called disorder-enhanced phosphorylation sites.<ref>PMID: 14960716</ref><ref>PMID: 18388127</ref>

===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.  

===Paxillin binding===

The <scene name='Alpha-parvin/Parvin/2'>scene on the right</scene> shows the superimposition of the three conformations that alpha-parvin adopts when 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 are not shown, but they 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 alpha-parvin 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^α positions.<ref>PMID: 18940607</ref>  

===ILK binding===

The <scene name='Alpha-parvin/Ilk_parvin/1'>scene on the left</scene> shows the complex ([[3kmw]]) of the kinase domain of integrin-linked kinase (ILK, red) bound to the C-terminal CH domain of alpha-parvin (blue). One can also see the molecule of ATP (green) and the space-fill representation of the magnesium atom (white). When we <scene name='Alpha-parvin/Ilk_parvin/2'>turn the structure</scene> so that the N-terminal helix (now orange) of the CH domain of alpha-parvin is pointing up, we can see that unlike paxillin LD motifs, ILK kinase domain does not bind to the N-terminal region of the CH domain, but rather near the <scene name='Alpha-parvin/Ilk_parvin/3'>long loop</scene> between helices αC and αE. Other parts of the CH domain are also involved in binding, leading to a high interface area (around 1900 Ų) characteristic of high-affinity complexes.<ref>PMID:20005845</ref> Interestingly, ILK, which was recently proved to lack kinase activity<ref>PMID:20005845</ref><ref>PMID: 20033063</ref>, binds alpha-parvin analogously to the way in which kinases bind their substrates, i.e. with its pseudoactive site. The binding is not dependent on the presence of ATP. On the ILK's side the binding is mediated primarily by <scene name='Alpha-parvin/Ilk_parvin/6'>one of the helices</scene> (αG) and a <scene name='Alpha-parvin/Ilk_parvin/5'>part of the activation loop</scene>. The complex formation is particularly dependent on <scene name='Alpha-parvin/Ilk_parvin/7'>methionine 402 and lysine 403</scene> in αG of ILK - if these two residues are mutated to alanines, the complex formation is completely abolished. These residues are involved in many interactions with alpha-parvin (one of them, a hydrogen bond to asparagine 280, is shown) or water molecules (one of them shown as a pink dot).

==References==

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