| Structural highlights
3aa1 is a 3 chain structure with sequence from Chick. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 1izn, 3aa0, 3aa6, 3aa7, 3aaa, 3aae |
| Gene: | CAPZA1 (CHICK), CAPZB (CHICK) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[CAZA1_CHICK] F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. CapZ may mediate the attachment of the barbed ends of actin filaments to the Z-line. [PKHO1_HUMAN] Plays a role in the regulation of the actin cytoskeleton through its interactions with actin capping protein (CP). May function to target CK2 to the plasma membrane thereby serving as an adapter to facilitate the phosphorylation of CP by protein kinase 2 (CK2). Appears to target ATM to the plasma membrane. Appears to also inhibit tumor cell growth by inhibiting AKT-mediated cell-survival. Also implicated in PI3K-regulated muscle differentiation, the regulation of AP-1 activity (plasma membrane bound AP-1 regulator that translocates to the nucleus) and the promotion of apoptosis induced by tumor necrosis factor TNF. When bound to PKB, it inhibits it probably by decreasing PKB level of phosphorylation.[1] [2] [3] [4] [5] [6] [7] [CAPZB_CHICK] F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. May play a role in the regulation of cell morphology and cytoskeletal organization.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The actin capping protein (CP) tightly binds to the barbed end of actin filaments, thus playing a key role in actin-based lamellipodial dynamics. V-1 and CARMIL proteins directly bind to CP and inhibit the filament capping activity of CP. V-1 completely inhibits CP from interacting with the barbed end, whereas CARMIL proteins act on the barbed end-bound CP and facilitate its dissociation from the filament (called uncapping activity). Previous studies have revealed the striking functional differences between the two regulators. However, the molecular mechanisms describing how these proteins inhibit CP remains poorly understood. Here we present the crystal structures of CP complexed with V-1 and with peptides derived from the CP-binding motif of CARMIL proteins (CARMIL, CD2AP, and CKIP-1). V-1 directly interacts with the primary actin binding surface of CP, the C-terminal region of the alpha-subunit. Unexpectedly, the structures clearly revealed the conformational flexibility of CP, which can be attributed to a twisting movement between the two domains. CARMIL peptides in an extended conformation interact simultaneously with the two CP domains. In contrast to V-1, the peptides do not directly compete with the barbed end for the binding surface on CP. Biochemical assays revealed that the peptides suppress the interaction between CP and V-1, despite the two inhibitors not competing for the same binding site on CP. Furthermore, a computational analysis using the elastic network model indicates that the interaction of the peptides alters the intrinsic fluctuations of CP. Our results demonstrate that V-1 completely sequesters CP from the barbed end by simple steric hindrance. By contrast, CARMIL proteins allosterically inhibit CP, which appears to be a prerequisite for the uncapping activity. Our data suggest that CARMIL proteins down-regulate CP by affecting its conformational dynamics. This conceptually new mechanism of CP inhibition provides a structural basis for the regulation of the barbed end elongation in cells.
Two distinct mechanisms for actin capping protein regulation--steric and allosteric inhibition.,Takeda S, Minakata S, Koike R, Kawahata I, Narita A, Kitazawa M, Ota M, Yamakuni T, Maeda Y, Nitanai Y PLoS Biol. 2010 Jul 6;8(7):e1000416. PMID:20625546[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Safi A, Vandromme M, Caussanel S, Valdacci L, Baas D, Vidal M, Brun G, Schaeffer L, Goillot E. Role for the pleckstrin homology domain-containing protein CKIP-1 in phosphatidylinositol 3-kinase-regulated muscle differentiation. Mol Cell Biol. 2004 Feb;24(3):1245-55. PMID:14729969
- ↑ Zhang L, Xing G, Tie Y, Tang Y, Tian C, Li L, Sun L, Wei H, Zhu Y, He F. Role for the pleckstrin homology domain-containing protein CKIP-1 in AP-1 regulation and apoptosis. EMBO J. 2005 Feb 23;24(4):766-78. Epub 2005 Feb 10. PMID:15706351 doi:http://dx.doi.org/10.1038/sj.emboj.7600532
- ↑ Canton DA, Olsten ME, Kim K, Doherty-Kirby A, Lajoie G, Cooper JA, Litchfield DW. The pleckstrin homology domain-containing protein CKIP-1 is involved in regulation of cell morphology and the actin cytoskeleton and interaction with actin capping protein. Mol Cell Biol. 2005 May;25(9):3519-34. PMID:15831458 doi:http://dx.doi.org/10.1128/MCB.25.9.3519-3534.2005
- ↑ Zhang L, Tie Y, Tian C, Xing G, Song Y, Zhu Y, Sun Z, He F. CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM. Cell Signal. 2006 Sep;18(9):1386-95. Epub 2005 Dec 1. PMID:16325375 doi:http://dx.doi.org/10.1016/j.cellsig.2005.10.017
- ↑ Canton DA, Olsten ME, Niederstrasser H, Cooper JA, Litchfield DW. The role of CKIP-1 in cell morphology depends on its interaction with actin-capping protein. J Biol Chem. 2006 Nov 24;281(47):36347-59. Epub 2006 Sep 20. PMID:16987810 doi:http://dx.doi.org/10.1074/jbc.M607595200
- ↑ Zhang L, Tang Y, Tie Y, Tian C, Wang J, Dong Y, Sun Z, He F. The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling. Cell Signal. 2007 May;19(5):932-44. Epub 2006 Nov 17. PMID:17197158 doi:http://dx.doi.org/10.1016/j.cellsig.2006.11.002
- ↑ Tokuda E, Fujita N, Oh-hara T, Sato S, Kurata A, Katayama R, Itoh T, Takenawa T, Miyazono K, Tsuruo T. Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo. Cancer Res. 2007 Oct 15;67(20):9666-76. PMID:17942896 doi:http://dx.doi.org/10.1158/0008-5472.CAN-07-1050
- ↑ Takeda S, Minakata S, Koike R, Kawahata I, Narita A, Kitazawa M, Ota M, Yamakuni T, Maeda Y, Nitanai Y. Two distinct mechanisms for actin capping protein regulation--steric and allosteric inhibition. PLoS Biol. 2010 Jul 6;8(7):e1000416. PMID:20625546 doi:10.1371/journal.pbio.1000416
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