Group:MUZIC:CapZ: Difference between revisions
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Cap Z was shown to be a stable heterodimer with α and β subunits of 286 and 277 residues, respectively. It is a mixed α-helix and β-sheet protein. CapZ has an elongated structure, with overall dimensions of~90 x 50 x55 Å. The capZ dimer has a pseudo two-fold symmetry, with the monomers joining together to form a central 10-stranded antiparallel <scene name='User:Mara_Camelia_Rusu/Workbench/CapZ/Central_b_sheet/1'>a central 10-stranded β-sheet</scene>. This creates an elongated molecule with the N- and C-terminus of each monomer on opposite faces of the central β -sheet. The C-termini of the subdomains are at opposite ends of the elongated molecule. | Cap Z was shown to be a stable heterodimer with α and β subunits of 286 and 277 residues, respectively. It is a mixed α-helix and β-sheet protein. CapZ has an elongated structure, with overall dimensions of~90 x 50 x55 Å. The capZ dimer has a pseudo two-fold symmetry, with the monomers joining together to form a central 10-stranded antiparallel <scene name='User:Mara_Camelia_Rusu/Workbench/CapZ/Central_b_sheet/1'>a central 10-stranded β-sheet</scene>. This creates an elongated molecule with the N- and C-terminus of each monomer on opposite faces of the central β -sheet. The C-termini of the subdomains are at opposite ends of the elongated molecule. | ||
One Cap Z heterodimer appears to be able to bind two actin molecules; this may explain why it is selective for the F-actin barbed end as opposed to monomeric G-actin. Cap Z is thought to bind between actin subdomains 1 and 3 (the barbed-end). Cap Z also binds a spectrin domain of α-actinin and the C-terminus of nebulin < | One Cap Z heterodimer appears to be able to bind two actin molecules; this may explain why it is selective for the F-actin barbed end as opposed to monomeric G-actin. Cap Z is thought to bind between actin subdomains 1 and 3 (the barbed-end). Cap Z also binds a spectrin domain of α-actinin and the C-terminus of nebulin <ref>PMID:15583864</ref>. | ||
== Function == | == Function == | ||
Capping protein binds to the barbed end with high affinity (Kd > 1 nM) and the stoichiometry is 1:1 and it prevents the loss and addition of actin monomers. Cap Z is important in the dynamics of actin filaments as it is crucial for rapid filament elongation as a response to signaling. It does so by blocking the barbed ends, thus ensuring a high steady state concentration of G-actin in the cytoplasm < | Capping protein binds to the barbed end with high affinity (Kd > 1 nM) and the stoichiometry is 1:1 and it prevents the loss and addition of actin monomers. Cap Z is important in the dynamics of actin filaments as it is crucial for rapid filament elongation as a response to signaling. It does so by blocking the barbed ends, thus ensuring a high steady state concentration of G-actin in the cytoplasm <ref>PMID:12660160</ref>. The absence of capping protein prevented the reconstruction of motility in ''Shigella'' and ''Listeria'', ''in vitro''. | ||
CapZ plays a role in targeting the actin filaments to other structural components. The sarcomeric isoform interacts with α-actinin and anchors the thin filament system to the Z-disk < | CapZ plays a role in targeting the actin filaments to other structural components. The sarcomeric isoform interacts with α-actinin and anchors the thin filament system to the Z-disk <ref>PMID:16416311</ref> | ||
Small interference RNA (siRNA) studies showed that knockdown of nebulin in chick skeletal myotubes leads to a reduction of assembled CapZ and a loss of the characteristic uniform alignment of the barbed ends of F-actin and this suggests that the interaction of Cap Z and nebulin plays a very important role in Z-disk architecture < | Small interference RNA (siRNA) studies showed that knockdown of nebulin in chick skeletal myotubes leads to a reduction of assembled CapZ and a loss of the characteristic uniform alignment of the barbed ends of F-actin and this suggests that the interaction of Cap Z and nebulin plays a very important role in Z-disk architecture <ref>PMID:18272787</ref>. | ||
Cap Z regulates the activity of cardiac protein kinase C (PKC): down regulation of Cap Z leads to a decrease and alteration of the PKC signaling pathways. Cardiac Cap Z regulates binding of PKC II to the myofilaments with effects on cardiac contractility <references/>[http://www.jbc.org/content/286/12/9897.abstract]. | Cap Z regulates the activity of cardiac protein kinase C (PKC): down regulation of Cap Z leads to a decrease and alteration of the PKC signaling pathways. Cardiac Cap Z regulates binding of PKC II to the myofilaments with effects on cardiac contractility <references/>[http://www.jbc.org/content/286/12/9897.abstract]. | ||
Other binding partners of Cap Z include the CARMIL protein which further interacts with Arp complex2/3 and myosin I, both of which are key players in actin based cell motility <references/>[http://www.ncbi.nlm.nih.gov/pubmed/12660160]. | Other binding partners of Cap Z include the CARMIL protein which further interacts with Arp complex2/3 and myosin I, both of which are key players in actin based cell motility <references/>[http://www.ncbi.nlm.nih.gov/pubmed/12660160]. | ||
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==References== | ==References== | ||
[[Category: actin binding proteins, actin regulation, CapZ, actin capping protein]] | [[Category: actin binding proteins, actin regulation, CapZ, actin capping protein]] | ||
Revision as of 11:44, 24 June 2011
CapZ (Actin Capping Protein, CP)CapZ (Actin Capping Protein, CP)
CapZ is expressed in all eukaryotic cells. It binds to the fast growing barbed ends of actin filaments and blocks G-actin association and disassociation, thus regulating actin filament dynamics. In skeletal muscle it localizes at the Z-disk. Cap Z is a heterodimer composed of two subunits and and there are at least two isoforms of each of the subunits. In cardiomyocites the β1 containing isoform localizes to the Z-disk and β2 containing isoform localizes to the cell periphery and intercalated disc. The crystal structure of the sarcomeric form has been resolved to a resolution of 2.1 Å by X-ray crystallography (1IZN). [1]
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Template:ABSTRACT PUBMED 12660160
StructureStructure
Cap Z was shown to be a stable heterodimer with α and β subunits of 286 and 277 residues, respectively. It is a mixed α-helix and β-sheet protein. CapZ has an elongated structure, with overall dimensions of~90 x 50 x55 Å. The capZ dimer has a pseudo two-fold symmetry, with the monomers joining together to form a central 10-stranded antiparallel . This creates an elongated molecule with the N- and C-terminus of each monomer on opposite faces of the central β -sheet. The C-termini of the subdomains are at opposite ends of the elongated molecule. One Cap Z heterodimer appears to be able to bind two actin molecules; this may explain why it is selective for the F-actin barbed end as opposed to monomeric G-actin. Cap Z is thought to bind between actin subdomains 1 and 3 (the barbed-end). Cap Z also binds a spectrin domain of α-actinin and the C-terminus of nebulin [2].
FunctionFunction
Capping protein binds to the barbed end with high affinity (Kd > 1 nM) and the stoichiometry is 1:1 and it prevents the loss and addition of actin monomers. Cap Z is important in the dynamics of actin filaments as it is crucial for rapid filament elongation as a response to signaling. It does so by blocking the barbed ends, thus ensuring a high steady state concentration of G-actin in the cytoplasm [3]. The absence of capping protein prevented the reconstruction of motility in Shigella and Listeria, in vitro. CapZ plays a role in targeting the actin filaments to other structural components. The sarcomeric isoform interacts with α-actinin and anchors the thin filament system to the Z-disk [4] Small interference RNA (siRNA) studies showed that knockdown of nebulin in chick skeletal myotubes leads to a reduction of assembled CapZ and a loss of the characteristic uniform alignment of the barbed ends of F-actin and this suggests that the interaction of Cap Z and nebulin plays a very important role in Z-disk architecture [5].
Cap Z regulates the activity of cardiac protein kinase C (PKC): down regulation of Cap Z leads to a decrease and alteration of the PKC signaling pathways. Cardiac Cap Z regulates binding of PKC II to the myofilaments with effects on cardiac contractility
- ↑ Yamashita A, Maeda K, Maeda Y. Crystal structure of CapZ: structural basis for actin filament barbed end capping. EMBO J. 2003 Apr 1;22(7):1529-38. PMID:12660160 doi:10.1093/emboj/cdg167
- ↑ Au Y. The muscle ultrastructure: a structural perspective of the sarcomere. Cell Mol Life Sci. 2004 Dec;61(24):3016-33. PMID:15583864 doi:10.1007/s00018-004-4282-x
- ↑ Yamashita A, Maeda K, Maeda Y. Crystal structure of CapZ: structural basis for actin filament barbed end capping. EMBO J. 2003 Apr 1;22(7):1529-38. PMID:12660160 doi:10.1093/emboj/cdg167
- ↑ Frank D, Kuhn C, Katus HA, Frey N. The sarcomeric Z-disc: a nodal point in signalling and disease. J Mol Med. 2006 Jun;84(6):446-68. Epub 2006 Jan 17. PMID:16416311 doi:10.1007/s00109-005-0033-1
- ↑ Pappas CT, Bhattacharya N, Cooper JA, Gregorio CC. Nebulin interacts with CapZ and regulates thin filament architecture within the Z-disc. Mol Biol Cell. 2008 May;19(5):1837-47. Epub 2008 Feb 13. PMID:18272787 doi:10.1091/mbc.E07-07-0690
[1].
Other binding partners of Cap Z include the CARMIL protein which further interacts with Arp complex2/3 and myosin I, both of which are key players in actin based cell motility [2]. In vivo the capping of actin filaments is regulated by second messengers PIP and PIP 2 (Phosphatidylinositol 4,5-bisphosphate), upon signal transduction these molecules promote removal of Cap Z from actin filaments [3].
Actin binding modelActin binding model
Proposed by Narita et al [4]
First, CP is attracted to the barbed-end of the actin filament through the electrostatic interactions between the basic residues, which are mainly but not exclusively on/around the α-tentacle and the acidic residues on the extreme surface at the barbed-end of the actin filament. The electrostatic interactions through the α-tentacle may be the major determining factors of the on-rate of the binding. This is because the deletion of the β-tentacle altered only the off-rate of the binding, without changing the on-rate. In contrast, the deletion of the a-tentacle reduced both the on- and off rates. Second, the β-tentacle finds the hydrophobic binding site on the front surface of actin. The binding of the b-tentacle acts as a lock, and thus reduces the off-rate as suggested previously. This two-step binding mechanism implies that the binding is possible even without the β-tentacle. This is because the first step alone fulfills two requirements for the barbed-end capping: the recognition of the barbed-end and the inhibition of polymerization and depolymerization.
Resolved structuresResolved structures
3LK2 - CapZ + CPI motif of CARMIL
3LK3 - CPI and CSI motifs from CARMIL
3LK4 - capZ + CD2AP