Parvin: Difference between revisions
No edit summary |
No edit summary |
||
| Line 10: | Line 10: | ||
Alpha-parvin is thus a component of the adhesome, but a more basic unit of which it is part is the IPP (ILK-PINCH-parvin) complex. The central component of this complex, [[integrin-linked kinase|ILK]], binds both [[PINCH]] and alpha-parvin, which do not interact directly with each other, and it is by means of ILK's pseudokinase domain that the complex is recruited to the cytoplasmic tail of integrins. The IPP complex is important for the correct FA assembly and promotes anti-apoptotic signalling<ref>PMID: 12960424</ref>. Alpha-parvin is also known to interact with a number of other proteins, including F-actin<ref>PMID: 11171322</ref>, paxillin<ref>PMID: 18508764</ref><ref>PMID: 18940607</ref>, paxillin's homologue HIC5<ref>PMID: 11134073</ref>, TESK1<ref>PMID: 15817463</ref>, CdGAP<ref>PMID: 16860736</ref> and alphaPIX<ref>PMID: 16860736</ref>. | Alpha-parvin is thus a component of the adhesome, but a more basic unit of which it is part is the IPP (ILK-PINCH-parvin) complex. The central component of this complex, [[integrin-linked kinase|ILK]], binds both [[PINCH]] and alpha-parvin, which do not interact directly with each other, and it is by means of ILK's pseudokinase domain that the complex is recruited to the cytoplasmic tail of integrins. The IPP complex is important for the correct FA assembly and promotes anti-apoptotic signalling<ref>PMID: 12960424</ref>. Alpha-parvin is also known to interact with a number of other proteins, including F-actin<ref>PMID: 11171322</ref>, paxillin<ref>PMID: 18508764</ref><ref>PMID: 18940607</ref>, paxillin's homologue HIC5<ref>PMID: 11134073</ref>, TESK1<ref>PMID: 15817463</ref>, CdGAP<ref>PMID: 16860736</ref> and alphaPIX<ref>PMID: 16860736</ref>. | ||
[[Image:Alpha_parvin.png|thumb|434px|right|Alpha-parvin domain composition and regions involved in the interactions with the binding partners]] | |||
===Alpha-parvin phosphorylation and cell migration=== | ===Alpha-parvin phosphorylation and cell migration=== | ||
Alpha-parvin possesses 6 putative proline-directed serine/threonine phosphorylation targets (residues 4, 8, 14, 16, 19, 61), of which serines 4 and 8 were shown to be the most important. Phosphorylation of alpha-parvin at serines 4 and 8 is correlated with the tightly regulated process of FA turnover during cell migration. Firstly, phosphorylation of these residues by cyclin B1/cdc2 is observed in the context of mitosis, whereby it contributes to FA disassembly required for cell-rounding prior to cell division, suggesting it may cause a similar effect during cell migration.<ref>PMID: 11931650</ref> Indeed, in migrating cells these residues are observed to be phosphorylated<ref>PMID: 15353548</ref>, likely as a result of MAP kinase<ref>PMID: 14636584</ref> and/or [[PI3K]]<ref>PMID: 12960424</ref>. Secondly, phosphomimetic mutations of serines 4 and 8 to aspartates result in faster migration and spreading, while mutations preventing phosphorylation impair these processes.<ref>PMID: 15353548</ref> Finally, as has already been mentioned in the introduction, knock-out mice phenotype (embryonic lethality due to severe cardiovascular defects) suggests alpha-parvin deficiency results in impaired directional migration of endothelial cells during embryonic development, heart development in particular.<ref>PMID: 19798050</ref> The macroscopic effects of alpha-parvin phosphorylation likely result from the altered affinity for its binding partners. So far it has been demonstrated that phosphorylation at serines 4 and 8 affects binding of alpha-parvin to TESK1 and CdGAP. When TESK1 is bound to alpha-parvin it is prevented from severing actin fibres. TESK1 is thought to be released from inhibition upon alpha-parvin phosphorylation and this can contribute to the decomposition of actin fibres and FA disassembly.<ref>PMID: 15817463</ref> CdGAP, on the other hand, is involved in the regulation of small GTPase signalling, which accounts for changes in cytoskeletal contractability during cell migration.<ref>PMID: 16860736</ref> Evidence suggesting that also the interaction with ILK is affected by phosphorylation is not strong<ref>PMID: 15872073</ref><ref>PMID: 12960424</ref>, but it is likely that this or yet other binding partners bind in the phosphorylation-dependent manner. | Alpha-parvin possesses 6 putative proline-directed serine/threonine phosphorylation targets (residues 4, 8, 14, 16, 19, 61), of which serines 4 and 8 were shown to be the most important. Phosphorylation of alpha-parvin at serines 4 and 8 is correlated with the tightly regulated process of FA turnover during cell migration. Firstly, phosphorylation of these residues by cyclin B1/cdc2 is observed in the context of mitosis, whereby it contributes to FA disassembly required for cell-rounding prior to cell division, suggesting it may cause a similar effect during cell migration.<ref>PMID: 11931650</ref> Indeed, in migrating cells these residues are observed to be phosphorylated<ref>PMID: 15353548</ref>, likely as a result of MAP kinase<ref>PMID: 14636584</ref> and/or [[PI3K]]<ref>PMID: 12960424</ref>. Secondly, phosphomimetic mutations of serines 4 and 8 to aspartates result in faster migration and spreading, while mutations preventing phosphorylation impair these processes.<ref>PMID: 15353548</ref> Finally, as has already been mentioned in the introduction, knock-out mice phenotype (embryonic lethality due to severe cardiovascular defects) suggests alpha-parvin deficiency results in impaired directional migration of endothelial cells during embryonic development, heart development in particular.<ref>PMID: 19798050</ref> The macroscopic effects of alpha-parvin phosphorylation likely result from the altered affinity for its binding partners. So far it has been demonstrated that phosphorylation at serines 4 and 8 affects binding of alpha-parvin to TESK1 and CdGAP. When TESK1 is bound to alpha-parvin it is prevented from severing actin fibres. TESK1 is thought to be released from inhibition upon alpha-parvin phosphorylation and this can contribute to the decomposition of actin fibres and FA disassembly.<ref>PMID: 15817463</ref> CdGAP, on the other hand, is involved in the regulation of small GTPase signalling, which accounts for changes in cytoskeletal contractability during cell migration.<ref>PMID: 16860736</ref> Evidence suggesting that also the interaction with ILK is affected by phosphorylation is not strong<ref>PMID: 15872073</ref><ref>PMID: 12960424</ref>, but it is likely that this or yet other binding partners bind in the phosphorylation-dependent manner. | ||
==Structure and function== | ==Structure and function== | ||
===Domain composition=== | ===Domain composition=== | ||
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> | 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> | ||