Summary: Adenylate cyclase associated (CAP) N terminal
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Cyclase-associated protein family Edit Wikipedia article
structure of the n-terminal domain of the adenylyl cyclase-associated protein (cap) from dictyostelium discoideum.
|SCOPe||1s0p / SUPFAM|
c-terminal domain of cyclase associated protein with pro 505 replaced by ser (p505s)
|SCOPe||1kq5 / SUPFAM|
In molecular biology, the cyclase-associated protein family (CAP) is a family of highly conserved actin-binding proteins present in a wide range of organisms including yeast, flies, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways. In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium discoideum (social amoeba), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly. In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity.
All CAPs appear to contain a C-terminal actin-binding domain that regulates actin remodelling in response to cellular signals and is required for normal cellular morphology, cell division, growth and locomotion in eukaryotes. CAP directly regulates actin filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localisation and the establishment of cell polarity. Actin exists both as globular (G) (monomeric) actin subunits and assembled into filamentous (F) actin. In cells, actin cycles between these two forms. Proteins that bind F-actin often regulate F-actin assembly and its interaction with other proteins, while proteins that interact with G-actin often control the availability of unpolymerised actin.
CAPs bind G-actin with high affinity through their CARP domain and promote nucleotide exchange from ADP-state back to polymerisable ATP-state form. The crystal structure of CARP domain bound to ADP-actin revealed CAPs have a unique dimeric binding mode to ADP-G-actin monomers. It was demonstrated that the C-terminus of CARP domain regulates the binding to ADP-G-actin monomers, and has a conserved role for efficient nucleotide exchange on actin monomers. In vivo studies demonstrated that nucleotide exchange performed by CAP/srv2 is crucial for normal actin cytoskeleton of budding yeast.
In addition to actin-binding, CAPs can have additional roles, and may act as bifunctional proteins. In Saccharomyces cerevisiae (Baker's yeast), CAP is a component of the adenylyl cyclase complex (Cyr1p) that serves as an effector of Ras during normal cell signalling. S. cerevisiae CAP functions to expose adenylate cyclase binding sites to Ras, thereby enabling adenylate cyclase to be activated by Ras regulatory signals. In Schizosaccharomyces pombe (Fission yeast), CAP is also required for adenylate cyclase activity, but not through the Ras pathway. In both organisms, the N-terminal domain is responsible for adenylate cyclase activation, but the S. cerevisiae and S. pombe N-termini cannot complement one another. Yeast CAPs are unique among the CAP family of proteins, because they are the only ones to directly interact with and activate adenylate cyclase. S. cerevisiae CAP has four major domains. In addition to the N-terminal adenylate cyclase-interacting domain, and the C-terminal actin-binding domain, it possesses two other domains: a proline-rich domain that interacts with Src homology 3 (SH3) domains of specific proteins, and a domain that is responsible for CAP oligomerisation to form multimeric complexes (although oligomerisation appears to involve the N- and C-terminal domains as well). The proline-rich domain interacts with profilin, a protein that catalyses nucleotide exchange on G-actin monomers and promotes addition to barbed ends of filamentous F-actin. Since CAP can bind profilin via a proline-rich domain, and G-actin via a C-terminal domain, it has been suggested that a ternary G-actin/CAP/profilin complex could be formed.
- Kotila T, Kogan K, Enkavi G, Guo S, Vattulainen I, Goode BL, Lappalainen P (May 2018). "Structural basis of actin monomer re-charging by cyclase-associated protein". Nature Communications. 9 (1): 1892. doi:10.1038/s41467-018-04231-7. PMC 5951797. PMID 29760438.
- Hubberstey AV, Mottillo EP (April 2002). "Cyclase-associated proteins: CAPacity for linking signal transduction and actin polymerization". FASEB Journal. 16 (6): 487â€“99. doi:10.1096/fj.01-0659rev. PMID 11919151.
- Deeks MJ, Rodrigues C, Dimmock S, Ketelaar T, Maciver SK, MalhÃ³ R, Hussey PJ (August 2007). "Arabidopsis CAP1 - a key regulator of actin organisation and development". Journal of Cell Science. 120 (Pt 15): 2609â€“18. doi:10.1242/jcs.007302. PMID 17635992.
- Freeman NL, Field J (February 2000). "Mammalian homolog of the yeast cyclase associated protein, CAP/Srv2p, regulates actin filament assembly". Cell Motility and the Cytoskeleton. 45 (2): 106â€“20. doi:10.1002/(SICI)1097-0169(200002)45:2<106::AID-CM3>3.0.CO;2-3. PMID 10658207.
- Hofmann A, Hess S, Noegel AA, Schleicher M, Wlodawer A (October 2002). "Crystallization of cyclase-associated protein from Dictyostelium discoideum". Acta Crystallographica D. 58 (Pt 10 Pt 2): 1858â€“61. doi:10.1107/S0907444902013306. PMID 12351838.
- Bertling E, Quintero-Monzon O, Mattila PK, Goode BL, Lappalainen P (April 2007). "Mechanism and biological role of profilin-Srv2/CAP interaction". Journal of Cell Science. 120 (Pt 7): 1225â€“34. doi:10.1242/jcs.000158. PMID 17376963.
- Bertling E, Hotulainen P, Mattila PK, Matilainen T, Salminen M, Lappalainen P (May 2004). "Cyclase-associated protein 1 (CAP1) promotes cofilin-induced actin dynamics in mammalian nonmuscle cells". Molecular Biology of the Cell. 15 (5): 2324â€“34. doi:10.1091/mbc.E04-01-0048. PMC 404026. PMID 15004221.
- Moriyama K, Yahara I (April 2002). "Human CAP1 is a key factor in the recycling of cofilin and actin for rapid actin turnover". Journal of Cell Science. 115 (Pt 8): 1591â€“601. PMID 11950878.
- Kotila T, Kogan K, Enkavi G, Guo S, Vattulainen I, Goode BL, Lappalainen P (May 2018). "Structural basis of actin monomer re-charging by cyclase-associated protein". Nature Communications. 9 (1): 1892. doi:10.1038/s41467-018-04231-7. PMC 5951797. PMID 29760438.
- Shima F, Okada T, Kido M, Sen H, Tanaka Y, Tamada M, Hu CD, Yamawaki-Kataoka Y, Kariya K, Kataoka T (January 2000). "Association of yeast adenylyl cyclase with cyclase-associated protein CAP forms a second Ras-binding site which mediates its Ras-dependent activation". Molecular and Cellular Biology. 20 (1): 26â€“33. doi:10.1128/mcb.20.1.26-33.2000. PMC 85033. PMID 10594005.
- Ksiazek D, Brandstetter H, Israel L, Bourenkov GP, Katchalova G, Janssen KP, Bartunik HD, Noegel AA, Schleicher M, Holak TA (September 2003). "Structure of the N-terminal domain of the adenylyl cyclase-associated protein (CAP) from Dictyostelium discoideum". Structure. 11 (9): 1171â€“8. doi:10.1016/S0969-2126(03)00180-1. PMID 12962635.
- Dodatko T, Fedorov AA, Grynberg M, Patskovsky Y, Rozwarski DA, Jaroszewski L, Aronoff-Spencer E, Kondraskina E, Irving T, Godzik A, Almo SC (August 2004). "Crystal structure of the actin binding domain of the cyclase-associated protein". Biochemistry. 43 (33): 10628â€“41. doi:10.1021/bi049071r. PMID 15311924.
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Adenylate cyclase associated (CAP) N terminal Provide feedback
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External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR013992
Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways [PUBMED:11919151, PUBMED:17635992, PUBMED:10658207, PUBMED:12351838]. In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly [PUBMED:17376963, PUBMED:15004221]. In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity.
All CAPs appear to contain a C-terminal actin-binding domain that regulates actin remodelling in response to cellular signals and is required for normal cellular morphology, cell division, growth and locomotion in eukaryotes. CAP directly regulates actin filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localisation and the establishment of cell polarity. Actin exists both as globular (G) (monomeric) actin subunits and assembled into filamentous (F) actin. In cells, actin cycles between these two forms. Proteins that bind F-actin often regulate F-actin assembly and its interaction with other proteins, while proteins that interact with G-actin often control the availability of unpolymerised actin. CAPs bind G-actin.
In addition to actin-binding, CAPs can have additional roles, and may act as bifunctional proteins. In Saccharomyces cerevisiae (Baker's yeast), CAP is a component of the adenylyl cyclase complex (Cyr1p) that serves as an effector of Ras during normal cell signalling. S. cerevisiae CAP functions to expose adenylate cyclase binding sites to Ras, thereby enabling adenylate cyclase to be activated by Ras regulatory signals. In Schizosaccharomyces pombe (Fission yeast), CAP is also required for adenylate cyclase activity, but not through the Ras pathway. In both organisms, the N-terminal domain is responsible for adenylate cyclase activation, but the S cerevisiae and S. pombe N-termini cannot complement one another. Yeast CAPs are unique among the CAP family of proteins, because they are the only ones to directly interact with and activate adenylate cyclase [PUBMED:10594005]. S. cerevisiae CAP has four major domains. In addition to the N-terminal adenylate cyclase-interacting domain, and the C-terminal actin-binding domain, it possesses two other domains: a proline-rich domain that interacts with Src homology 3 (SH3) domains of specific proteins, and a domain that is responsible for CAP oligomerisation to form multimeric complexes (although oligomerisation appears to involve the N- and C-terminal domains as well). The proline-rich domain interacts with profilin, a protein that catalyses nucleotide exchange on G-actin monomers and promotes addition to barbed ends of filamentous F-actin [PUBMED:17376963]. Since CAP can bind profilin via a proline-rich domain, and G-actin via a C-terminal domain, it has been suggested that a ternary G-actin/CAP/profilin complex could be formed.
This entry represents the N-terminal domain of CAP proteins. This domain has an all-alpha structure consisting of six helices in a bundle with a left-handed twist and an up-and-down topology [PUBMED:12962635].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||actin binding (GO:0003779)|
|Biological process||cytoskeleton organization (GO:0007010)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Author:||Finn RD , Bateman A|
|Number in seed:||163|
|Number in full:||1272|
|Average length of the domain:||72.30 aa|
|Average identity of full alignment:||33 %|
|Average coverage of the sequence by the domain:||14.72 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||20|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CAP_N domain has been found. There are 4 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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