A flagellar A-kinase anchoring protein with two amphipathic helices forms a structural scaffold in the radial spoke complex

Sivadas, Priyanka; Dienes, Jennifer M.; Maurice, Martin St.; Meek, William D.; Yang, Pinfen

doi:10.1085/jgp1406oia10

Cited by 5 publications

(9 citation statements)

References 51 publications

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“…The RS epitomizes the versatility of DD domains and their amphipathic helix partners (Gopal et al 2012;Sivadas et al 2012). The DD domains bring to molecular complexes RSPs in the head region are shaded in gray.…”

Section: Evolution Of Radial Spokesmentioning

confidence: 99%

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Radial Spokes—A Snapshot of the Motility Regulation, Assembly, and Evolution of Cilia and Flagella

Zhu

Liu

Yang

2016

Cold Spring Harb Perspect Biol

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Section: Evolution Of Radial Spokesmentioning

confidence: 99%

“…First of all, RSs nudge the CP to its central location (e.g., Sivadas et al 2012). The CP shifts from the central location when RSs are defective.…”

Section: Maintenance Of 9þ2 Axoneme Structural Stabilitymentioning

confidence: 99%

Radial Spokes—A Snapshot of the Motility Regulation, Assembly, and Evolution of Cilia and Flagella

Zhu

Liu

Yang

2016

Cold Spring Harb Perspect Biol

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“…The axoneme targeting domain has been shown to bind to the axoneme, probably in an indirect manner; 48 the AH R domain has been shown to directly interact with protein kinase A 47,49 and RSP11 (the ortholog of human ROPN1L, also named RSPH11). 49 The Dpy-30-domain-binding amphipathic helix (AH D ) has been shown to directly interact with RSP2 (the ortholog of human DYDC1) and RSP23 (the ortholog of human NME5, also named RSPH23), 50 whereas the three TQT-like domains have been found to interact directly with a LC8 (the ortholog of human DYNLL1) dimer. 51 As proposed by Sivadas et al, 50 RSP3, which is a RS-stalk protein, forms a dimer that constitutes the core of each RS and has two sites for anchoring RSP7 and RSP11 at the A-tubule of the outer-doublet side and RSP2 and RSP23 (two RS-neck proteins) at the central-pair side.…”

mentioning

confidence: 99%

RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes

Jeanson

Copin

Papon

et al. 2015

The American Journal of Human Genetics

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Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive condition resulting from structural and/or functional defects of the axoneme in motile cilia and sperm flagella. The great majority of mutations identified so far involve genes whose defects result in dynein-arm anomalies. By contrast, PCD due to CC/RS defects (those in the central complex [CC] and radial spokes [RSs]), which might be difficult to diagnose, remains mostly unexplained. We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects. RSPH3, whose ortholog in the flagellated alga Chlamydomonas reinhardtii encodes a RS-stalk protein, is mainly expressed in respiratory and testicular cells. Its protein product, which localizes within the cilia of respiratory epithelial cells, was undetectable in airway cells from an individual with RSPH3 mutations and in whom RSPH23 (a RS-neck protein) and RSPH1 and RSPH4A (RS-head proteins) were found to be still present within cilia. In the case of RSPH3 mutations, high-speed-videomicroscopy analyses revealed the coexistence of immotile cilia and motile cilia with movements of reduced amplitude. A striking feature of the ultrastructural phenotype associated with RSPH3 mutations is the near absence of detectable RSs in all cilia in combination with a variable proportion of cilia with CC defects. Overall, this study shows that RSPH3 mutations contribute to disease in more than 10% of PCD-affected individuals with CC/RS defects, thereby allowing an accurate diagnosis to be made in such cases. It also unveils the key role of RSPH3 in the proper building of RSs and the CC in humans.

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“…the two RS proteins (RSP7 and RSP11) contain the R2D2 domain (RII fold) -what is also known as the DPY30 domain. These proteins share a similar secondary and tertiary structure like other R2D2 proteins and also bind to amphipathic helices of AKAPs [16,20,21]. In yet another study, an AKAP interactor, MYC-binding protein-1 (MYCBP-1) was found to bind to the AH of AKAPs.…”

Section: R2d2-like Proteinsmentioning

confidence: 95%

“…And, the entire RS protein complex harbors features that are related to the PKA-AKAP signaling module. For example, (i) the N-terminus of RSP3 functions to anchor the entire RS to specific sites in the axoneme; (ii) RSP3 is known to form homodimer [15], and each of these monomers contains an AH for interacting with RSP7 or RSP11 [16], both containing the RII domain. Both these proteins lack any features required for cAMP signaling [17,18].…”

Section: A-kinase Anchoring Proteinsmentioning

confidence: 99%

MYC-Binding Protein-1 is an R2D2 Protein

D’Souza¹

2017

J Cell Signal

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Commentary '9+2' cilia/flagellaThe eukaryotic cilia/flagella have a '9+2' structure that is highly conserved in structure with 9 pair of outer microtubule doublets; one of these filaments is complete, and is known as the A microtubule; while the other microtubule is incomplete and is known as the B microtubule. These are present in the periphery and surround the two centrally placed microtubule singlets known as the central pair apparatus. These hair-like extracellular organelles can propel cells through an aqueous environment or also circulate the fluid surrounding them. This biological nano-machine without the membranous covering is known as the axoneme. With heterogeneity in their sizes (few μmm to few mm), these flexible extensions are conserved across evolution. A cross-section of the flagellum/cilium reveals the following sub-ciliary structures, the Outer Dynein Arms (ODA), Inner Dynein Arms (IDA), Dynein Regulatory Complex (DRC), Radial Spokes (RS) and the Central Pair (CP) apparatus that harbor several proteinaceous projections. These and other less evident structures are essentially protein complexes within the axoneme that operate in synchrony to generate the periodic beating that is typical of the flagella waves.It is known that the second messenger, cyclic adenosine monophosphate (cAMP) regulates flagellar movement. Further, the use of pharmacological inhibitors on isolated axonemes of various flagellar mutants that have been mutated in the ODA, IDA, DRC, RS and CP have implicated cAMP-dependent protein kinase (PKA) and other phosphoenzymes in the dynein-driven microtubule sliding [1][2][3][4][5][6]. The PKA holoenzyme is made up of two regulatory (R) and two catalytic (C) subunits. Inside the cell, it is always found anchored to a scaffold protein; namely, the A-Kinase Anchoring Protein (AKAP) via its R subunit. The high-affinity binding partners of the R subunit of PKA [7] that were first discovered in 1982 are now known to be present in several organisms. With the RII subunit as bait, AKAPs are conveniently identified using the classical overlay assay [8]. A-Kinase Anchoring ProteinsAll known AKAPs share little sequence homology; however, their common features include -a region for targeting it to a particular cellular location, an Amphipathic helix (AH) that binds to the Dimerization/Docking domain (D/D; or, R2D2 domain) of the PKA R subunit, and motifs other than these two for the recruitment of an array of molecules involved in signaling [9]. It is this AH that offers as one of the most important parameters for a protein to be designated as an AKAP. In fact, a recently conducted study used an in silico approach to determine AH-containing proteins that led to the identification of candidate AKAPs [10]. And, when RII overlays were performed in ciliated cells, a number of AKAPs were revealed; at least 7 were present in the fibrous sheath surrounding the mammalian sperm axonemes [11], one was found in the human respiratory tract cilia [12] and two (AKAP97 and AKAP240) in the Chlamydomonas flagellar...

show abstract

A flagellar A-kinase anchoring protein with two amphipathic helices forms a structural scaffold in the radial spoke complex

Cited by 5 publications

References 51 publications

Radial Spokes—A Snapshot of the Motility Regulation, Assembly, and Evolution of Cilia and Flagella

Radial Spokes—A Snapshot of the Motility Regulation, Assembly, and Evolution of Cilia and Flagella

RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes

MYC-Binding Protein-1 is an R2D2 Protein

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