Molecular in situ topology of Aczonin/Piccolo and associated proteins at the mammalian neurotransmitter release site
The protein machinery of neurotransmitter exocytosis requires efficient orchestration in space and time, for speed and precision of neurotransmission and also for synaptic ontogeny and plasticity. However, its spatial organization in situ is virtually unknown. Aczonin/Piccolo is a putative organizer...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 31; pp. E392 - E401 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
02.08.2011
National Acad Sciences |
Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
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Abstract | The protein machinery of neurotransmitter exocytosis requires efficient orchestration in space and time, for speed and precision of neurotransmission and also for synaptic ontogeny and plasticity. However, its spatial organization in situ is virtually unknown. Aczonin/Piccolo is a putative organizer protein of mammalian active zones. We determined by immunogold electron microscopy (EM) (i) the spatial arrangement (i.e., topology) of 11 segments of the Aczonin polypeptide in situ, and correlated it to (ii) the positioning of Aczonin-interacting domains of Bassoon, CAST/ELKS, Munc13, and RIM and (iii) the ultrastructurally defined presynaptic macromolecular aggregates known as dense projections and synaptic ribbons. At conventional synapses, Aczonin assumes a compact molecular topology within a layer 35 to 80 nm parallel to the plasma membrane (PM), with a "trunk" sitting on the dense projection top and a C-terminal "arm" extending down toward the PM and sideward to the dense projection periphery. At ribbon synapses, Aczonin occupies the whole ribbon area. Bassoon colocalizes with Aczonin at conventional synapses but not at ribbon synapses. At both conventional and ribbon synapses, CAST, Munc13, and RIM are segregated from Aczonin, closer to the PM, and Aczonin is positioned such that it may control the access of neurotransmitter vesicles to the fusion site. |
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AbstractList | The protein machinery of neurotransmitter exocytosis requires efficient orchestration in space and time, for speed and precision of neurotransmission and also for synaptic ontogeny and plasticity. However, its spatial organization in situ is virtually unknown. Aczonin/Piccolo is a putative organizer protein of mammalian active zones. We determined by immunogold electron microscopy (EM) (
i
) the spatial arrangement (i.e., topology) of 11 segments of the Aczonin polypeptide in situ, and correlated it to (
ii
) the positioning of Aczonin-interacting domains of Bassoon, CAST/ELKS, Munc13, and RIM and (
iii
) the ultrastructurally defined presynaptic macromolecular aggregates known as dense projections and synaptic ribbons. At conventional synapses, Aczonin assumes a compact molecular topology within a layer 35 to 80 nm parallel to the plasma membrane (PM), with a “trunk” sitting on the dense projection top and a C-terminal “arm” extending down toward the PM and sideward to the dense projection periphery. At ribbon synapses, Aczonin occupies the whole ribbon area. Bassoon colocalizes with Aczonin at conventional synapses but not at ribbon synapses. At both conventional and ribbon synapses, CAST, Munc13, and RIM are segregated from Aczonin, closer to the PM, and Aczonin is positioned such that it may control the access of neurotransmitter vesicles to the fusion site. The protein machinery of neurotransmitter exocytosis requires efficient orchestration in space and time, for speed and precision of neurotransmission and also for synaptic ontogeny and plasticity. However, its spatial organization in situ is virtually unknown. Aczonin/Piccolo is a putative organizer protein of mammalian active zones. We determined by immunogold electron microscopy (EM) (i) the spatial arrangement (i. e., topology) of 11 segments of the Aczonin polypeptide in situ, and correlated it to (ii) the positioning of Aczonin-interacting domains of Bassoon, CAST/ELKS, Munc13, and RIM and (iii) the ultrastructurally defined presynaptic macromolecular aggregates known as dense projections and synaptic ribbons. At conventional synapses, Aczonin assumes a compact molecular topology within a layer 35 to 80 nm parallel to the plasma membrane (PM), with a "trunk" sitting on the dense projection top and a C-terminal "arm" extending down toward the PM and sideward to the dense projection periphery. At ribbon synapses, Aczonin occupies the whole ribbon area. Bassoon colocalizes with Aczonin at conventional synapses but not at ribbon synapses. At both conventional and ribbon synapses, CAST, Munc13, and RIM are segregated from Aczonin, closer to the PM, and Aczonin is positioned such that it may control the access of neurotransmitter vesicles to the fusion site. The protein machinery of neurotransmitter exocytosis requires efficient orchestration in space and time, for speed and precision of neurotransmission and also for synaptic ontogeny and plasticity. However, its spatial organization in situ is virtually unknown. Aczonin/Piccolo is a putative organizer protein of mammalian active zones. We determined by immunogold electron microscopy (EM) (i) the spatial arrangement (i.e., topology) of 11 segments of the Aczonin polypeptide in situ, and correlated it to (ii) the positioning of Aczonin-interacting domains of Bassoon, CAST/ELKS, Munc13, and RIM and (iii) the ultrastructurally defined presynaptic macromolecular aggregates known as dense projections and synaptic ribbons. At conventional synapses, Aczonin assumes a compact molecular topology within a layer 35 to 80 nm parallel to the plasma membrane (PM), with a "trunk" sitting on the dense projection top and a C-terminal "arm" extending down toward the PM and sideward to the dense projection periphery. At ribbon synapses, Aczonin occupies the whole ribbon area. Bassoon colocalizes with Aczonin at conventional synapses but not at ribbon synapses. At both conventional and ribbon synapses, CAST, Munc13, and RIM are segregated from Aczonin, closer to the PM, and Aczonin is positioned such that it may control the access of neurotransmitter vesicles to the fusion site. [PUBLICATION ABSTRACT] The protein machinery of neurotransmitter exocytosis requires efficient orchestration in space and time, for speed and precision of neurotransmission and also for synaptic ontogeny and plasticity. However, its spatial organization in situ is virtually unknown. Aczonin/Piccolo is a putative organizer protein of mammalian active zones. We determined by immunogold electron microscopy (EM) ( i ) the spatial arrangement (i.e., topology) of 11 segments of the Aczonin polypeptide in situ, and correlated it to ( ii ) the positioning of Aczonin-interacting domains of Bassoon, CAST/ELKS, Munc13, and RIM and ( iii ) the ultrastructurally defined presynaptic macromolecular aggregates known as dense projections and synaptic ribbons. At conventional synapses, Aczonin assumes a compact molecular topology within a layer 35 to 80 nm parallel to the plasma membrane (PM), with a “trunk” sitting on the dense projection top and a C-terminal “arm” extending down toward the PM and sideward to the dense projection periphery. At ribbon synapses, Aczonin occupies the whole ribbon area. Bassoon colocalizes with Aczonin at conventional synapses but not at ribbon synapses. At both conventional and ribbon synapses, CAST, Munc13, and RIM are segregated from Aczonin, closer to the PM, and Aczonin is positioned such that it may control the access of neurotransmitter vesicles to the fusion site. Author Summary The model in Fig. P1 E shows that the molecular dimensions of Aczonin correspond strikingly to the sizes of dense projections (45 nm high) and synaptic vesicles (38 nm diameter). The “trunk-and-arm” topology in particular suggests that Aczonin acts as a gatekeeper for vesicles to access the plasma membrane from deep within the terminal before release. This notion is consistent with recent functional studies from other laboratories ( 4 , 5 ). Our work reveals, for a subset of presynaptic proteins, a well defined molecular organization at the neurotransmitter release site. Future research will aim to complete this model by determining the topologies of additional proteins and protein segments, and to study the molecular topologies of other specialized synapse types such as the neuromuscular junction. A particular challenge will be to observe this molecular machinery in motion during vesicle exocytosis. With its huge size, Aczonin was particularly promising as a potential organizer of the presynaptic molecular machinery. The protein's long polypeptide chain, were it an extended α-helical filament, could theoretically extend 20 vesicle diameters into the synaptic terminal. However, what is the spatial arrangement (i.e., the molecular topology) of this large molecule at the active zone? To investigate this topology, we raised antibodies against 11 recombinant partial sequences along the Aczonin polypeptide and used them as specific molecular probes, to label the corresponding segments of Aczonin in brain sections that we subsequently examined with EM. As seen in Fig. P1 A , Aczonin segments were detected at sharply defined distances from the presynaptic plasma membrane. We quantified localizations with morphometric measurements of the positions of several hundred immunolabel particles for each protein segment. The entire Aczonin molecule was found to occupy a layer of 35 to 80 nm parallel to the plasma membrane, with the N-terminal parts of the protein further away ( Fig. P1 B ) and the C-terminal part closer to the membrane ( Fig. P1 C ). Immunolabeling of Aczonin sequences combined with staining dense projections with heavy metals ( Fig. P1 B – D ) allowed us to also determine the lateral localizations relative to the central axis of dense projections. We found that the N-terminal sequences of Aczonin sit right above dense projections ( Fig. P1 B ) and constitute a “trunk,” whereas the C-terminal sequences reach in an “arm”-like manner toward the interval between dense projections ( Fig. P1 C ) where neurotransmitter vesicles are believed to fuse. These findings led us to the model illustrated in Fig. P1 E . Sequence region 7–6 of Aczonin is known to interact with the N-terminal regions of Munc13 and RIM, and the C-terminal part of Bassoon. Therefore, we also determined the localizations of these protein segments. The Bassoon C terminus colocalized very closely with the corresponding Aczonin region, whereas the RIM and Munc13 N termini ( Fig. P1 D ), as well as a segment of the voltage-gated calcium channel (another important player in neurotransmitter release), were significantly closer to the plasma membrane. We complemented these studies by determining the topology of Aczonin and its binding partners at a specialized synapse type: ribbon synapses of photoreceptor cells in the eye. Aczonin/Piccolo, Bassoon, CAST, Munc13, and RIM are among the presynaptic proteins that participate in neurotransmitter release. These molecules are large and complex (Aczonin and Bassoon are among the largest proteins known, with lengths of 5000 and 4000 aa, respectively), and can bind to many other proteins including each other, giving rise to a highly interconnected and interactive supramolecular assembly ( 3 ). In our study, we set out to explore the spatial organization of this assembly at the neurotransmitter release site using immunogold EM. Many proteins that contribute to neurotransmitter release have been identified in recent years ( 1 ), but our understanding of the mechanistic interplay between these proteins is still in its infancy. Moreover, it appears that these molecules are assembled in an organized fashion that enhances the speed and precision of protein interactions and turns them into small “molecular machines.” For example, electron microscopists discovered half a century ago that specific staining techniques can visualize presynaptic aggregates of regular size, shape, and spacing ( Fig. P1 B – D ) ( 2 ). Many researchers suspect that these aggregates, called dense projections, represent modular, structured assemblies of the neurotransmitter release machinery. Neurotransmitter release is very fast—an electrical signal can trigger membrane fusion in less than 1 ms—but at the same time highly controlled and regulated. This requires the precise interplay of hundreds of different proteins at defined patches of the presynaptic plasma membrane known as active zones. Modulating the quantities and properties of active zone proteins fine-tunes synaptic signaling for information processing and memory tasks. Disturbances in the function of active zone proteins have been implicated in medical disorders such as ALS, schizophrenia, depression, and diabetes. Synapses serve as junctions through which nerve cells send signals to other nerve cells, to muscle cells, or to hormone-secreting cells. At the end of a nerve fiber, a synaptic terminal ( Fig. P1 A ) contains a cluster of several hundred small membrane vesicles filled with neurotransmitter substances. Electrical signals arrive at the terminals and induce some of these vesicles to fuse with the presynaptic plasma membrane, which discharges the neurotransmitter into the synaptic cleft. Transmitter molecules can then bind to receptor proteins on the opposing postsynaptic membrane and induce a new electrical signal in the postsynaptic cell. |
Author | Hultqvist, Greta Limbach, Christoph Laue, Michael M Kilimann, Manfred W Hu, Bin Wang, Xiaolu Thiede, Nadine |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21712437$$D View this record in MEDLINE/PubMed https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-157245$$DView record from Swedish Publication Index |
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Notes | http://dx.doi.org/10.1073/pnas.1101707108 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Author contributions: M.W.K. designed research; C.L., M.M.L., X.W., B.H., N.T., and G.H. performed research; C.L., M.M.L., and M.W.K. analyzed data; and M.W.K. wrote the paper. 1Present address: Robert Koch-Institut, D-13353 Berlin, Germany. Edited by Nils Brose, Max Planck Institute for Experimental Medicine, Göttingen, Germany, and accepted by the Editorial Board June 7, 2011 (received for review January 30, 2011) 2Present address: Evotec NeuroScience, D-22525 Hamburg, Germany. |
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SubjectTerms | Adaptor Proteins, Signal Transducing - metabolism Animals Binding Sites Biological Sciences Cell Membrane - metabolism Cell Membrane - ultrastructure Cytoskeletal Proteins - metabolism electron microscopy exocytosis GTP-Binding Proteins - metabolism Immunoblotting Mammals MEDICIN MEDICINE Membranes Microscopy, Immunoelectron Molecular structure Multiprotein Complexes - metabolism Multiprotein Complexes - ultrastructure Nerve Tissue Proteins - metabolism Neuropeptides - metabolism Neurotransmitter Agents - metabolism Neurotransmitters ontogeny plasma membrane PNAS Plus polypeptides Protein Binding protein structure Proteins Rats Rats, Sprague-Dawley scaffolding protein space and time Synapses - metabolism Synapses - ultrastructure synaptic transmission topology |
Title | Molecular in situ topology of Aczonin/Piccolo and associated proteins at the mammalian neurotransmitter release site |
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