MYC-Binding Protein-1 is an R2D2 Protein

Jacinta S D Souza
2017 Journal of Cell Signaling  
Commentary '9+2' cilia/flagella The 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
more » ... elles 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]. All 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 axonemes [13] . The analysis of flagellar mutants lacking specific axonemal complexes revealed that AKAP97 is the radial spoke protein, RSP3; whereas, AKAP240 is localized in the CP. This finding indicates that both the RS and CP have a role in regulating dynein motors. Nevertheless, of the 23 proteins found to be present in the RS of the Chlamydomonas flagella, there is no resemblance whatsoever to the PKA C subunits [14] . 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] . Therefore, it is believed that the Chlamydomonas flagella RS utilizes the AKAP-PKA signaling module to tether different molecules for its functioning; but, may not utilize cAMP in its transduction. Figure 1 describes this basic signaling module. Figure 1 : The basic signaling module (AKAP-R2D2 proteins). This module is found all over cells, including the cilia and flagella of eukaryotes. Note that protein kinase A consists of 2 Regulatory and 2 catalytic subunits (R2D2). Domains on AKAP for tethering signaling molecules other than R2D2 exist. This entire module is normally anchored on to some organelle inside the cell.
doi:10.4172/2576-1471.1000161 fatcat:sm56odkvgrh5jbs6v2udnb23ga