Most studied members of naturally-occurring α-conotoxins.
1. Introduction
The chapter briefly covers the history of protein and peptide neurotoxins in research on nicotinic acetylcholine receptors (nAChR). It all started with a great help of α-bungarotoxin and other similar α-neurotoxins from snake venoms in isolation from the
A generous source for sophisticated tools in research on nAChRs is combinatorial peptide libraries from the venoms of
The chapter briefly summarizes information on the spatial organization and subunit composition of different nAChR subtypes, but considers in more detail important contributions of peptide and protein neurotoxins into elucidation of the topography of the nAChR binding sites. The information mainly came from the X-ray structures of their complexes with the acetylcholine-binding protein (AChBP), an excellent structural model of the ligand-binding domain of nAChRs. These complexes are considered as initial blocks for design of novel drugs.
2. Muscle-type, neuronal and “non-neuronal” nAChRs — Brief overview
Before considering in detail protein and peptide neurotoxins on which the Chapter is mostly focused, it is reasonable to give very shortly the information about various types of nAChR which will make easier later discussions of the specificity of one or another toxin to a particular nAChR subtype.
As mentioned in the Introduction, α-bungarotoxin made possible identification and isolation in a pure form of the nAChR from the
Earlier it was thought that the ligand-binding sites of nAChRs lie within the α-subunits, hence there should be two binding sites on the muscle-type nAChRs. To-day we know that, indeed, the main contributions to binding of agonists or competitive antagonists are donated by the α-subunits. Moreover, even isolated α-subunit and its fragment in the amino-acid region 170-200 can bind α-bungarotoxin, although with lower affinity than the whole-size receptors [5,6]. However, now it is well established that the binding sites are situated at the interfaces of the α-subunits with their neighbors, and it is the variability of functional groups brought to the binding sites by less conservative “non-alpha” subunits which underlies the differences in specificity between individual nAChR subtypes [4].
What are the types and subtypes of nicotinic acetylcholine receptors? As mentioned above, binding of radioactive α-bungarotoxin to brain membranes finally brought to life the nAChR presently known as homopentameric α7 nAChR that is composed of five identical α7-subunits. Thus, we have an example of homooligomeric receptor belonging to the family of neuronal nAChRs. Neuronal heteromeric nAChRs are composed of two types of subunits: α and β. At present there are 9 types of neuronal α-subunits (α2-α10) and three types of β subunits (β2-β4); α and β subunits in the muscle-type receptors presumed to be α1 and β1 ones. The characteristic feature of α-subunit is a vicinal disulfide between two neighboring Cys residues in the binding site (Cys192-Cys193 in the amino-acid sequence of the
Structurally, the
The first and the most direct structural evidence for a common three-dimensional organization of all nAChRs came from the crystal structure of AChBP [10]. Today even more convincing are the recently solved high-resolution X-ray structures of the whole-size prokaryotic membrane proteins belonging to the same superfamily of Cys-loop ligand-gated ion channels as nAChRs [11-13]. These proteins, each composed of 5 identical subunits, do not have large cytoplasmic domains (which apparently made their crystallization much more simple than of nAChRs or other mammalian Cys-loop receptors), but in the transmembrane and ligand-binding domains they are surprisingly similar to
3. Snake venom neurotoxins utilized in research on nAChRs — Primary and three-dimensional structure
The word “toolbox“ in the chapter title in the first place is related to the snake venom proteins, at least historically. It was the component of
3.1. α-Neurotoxins
There are two structural types of α-neurotoxins: short-chain α-neurotoxins (60-62 amino acid residues, 4 disulfide bridges) and long-chain ones (66-75 amino acid residues, 5 disulfide bonds). The first X-ray structures have been determined for the short-chain α-neurotoxins, namely for erabutoxins a and b [18,19] (see Figure 2, A). The molecule has three loops, with a predominant β-structure, fixed in the space by 4 disulfide bridges forming a sort of a knot. This folding gave the name of “three-finger proteins” to α-neurotoxins. Later spatial structures have been determined both by NMR and X-ray crystallography for different short- and long-chain α-neurotoxins, including α-bungarotoxin [20,21]. Long-chain α-neurotoxins have the same three -finger folding as the short ones, but contain a longer C-terminal tail and an additional 5th disulfide in the central loop II (Figure 2, B). In the structures of some long-chain α-neurotoxins (α-bungarotoxin, α-cobratoxin [22] or neurotoxin I from
One of the characteristic features of α-neurotoxins is the stability of their three-dimensional structure fixed by 4 or 5 disulfide bridges. This conclusion is supported by high similarity of spatial structures determined by NMR at different conditions (varying pH and temperatures) and by X-ray crystallography. This may be one of the crucial factors explaining high efficiency of α-neurotoxin interactions with their targets, nicotinic acetylcholine receptors. As will be shown later, α-neurotoxins essentially preserve their conformation in complexes with the AChBP [24], with the ligand-binding domain of individual α1 subunit of nAChR [25] and with the chimera of AChBP and α7 nAChR extracellular domain [26].
3.2. Dimeric three-finger neurotoxins
First of all, we should mention here κ-bungarotoxins and several homologous neurotoxins which are dimers, but do not have covalent intermolecular bonds between monomers [27]. Each monomer is very similar to a typical long-chain α-neurotoxin: the same additional 5th disulfide at the tip of the central loop II, but a slightly shorter C-terminal tail (total number of amino acid residues 66 but not 75 as in α-bungarotoxin) (see Figure 2, C). The molecular targets of κ-bungarotoxins are neuronal nAChRs, but contrary to α-neurotoxins they have high affinity to neuronal α3β2 nAChR [28]. Interestingly, it was established about 20 years ago that there is one common property of α-neurotoxins and κ-neurotoxins, namely the additional disulfide in the loop II is essential for recognition of neuronal nAChRs. It was found that selective reduction of that disulfide and subsequent alkylation or removal of the respective cysteines in both types of toxins abolished their high affinity binding to α7 and α3β2 nAChRs, respectively (without decreasing the affinity of long-chain α-neurotoxins to muscle-type nAChRs [29,30]). On the other hand, introduction of additional disulfide into the central loop of short-chain α-neurotoxins considerably increased their affinity for α7 nAChR [31,32].
It is not yet absolutely clear why κ-bungarotoxins have preference for heteromeric nAChRs. There was a hypothesis that an important role in selectivity of κ-bungarotoxins towards α3β2 nAChRs belongs to the residue Lys26 [24]. However, its introduction to α-neurotoxin having a high affinity for α7 nAChRs only decreased considerably binding to this receptor but did not bring any affinity for α3β2 nAChRs [32]. Apparently, dimerization as such is important to force a protein, composed of two classical α-neurotoxins, to recognize a heteromeric neuronal nAChRs as can be seen on the example of other recently discovered dimeric neurotoxins.
One toxin, haditoxin from the King cobra venom [33] looks very similar to κ-bungarotoxin. Haditoxin is a non-covalent dimer composed of two short-chain α-neurotoxins, rather than of long-chain ones, and the monomers adopt a topological arrangement (Figure 2, D) reminiscent of that observed earlier for monomers in κ-bungarotoxin. Haditoxin can block not only muscle-type nAChRs, as typically observed for short-chain α-neurotoxins, but surprisingly it also blocks homooligomeric α7 and heterooligomeric α3β2 nAChRs. This finding appears to be in contradiction with the earlier found necessity of the additional disulfide in the central loop for recognition of neuronal nAChRs. However, it should be kept in mind that blocking of neuronal nAChRs by haditoxin was observed only at very high toxin concentrations [33]. It should be also mentioned that, strictly speaking, haditoxin cannot be assigned to classical short-chain α-neurotoxins because its homology to erabutoxin is only 50%, whereas it is 75-80% with the muscarinic toxin-like proteins (MTLP) having different targets [34].
Novel types of dimeric α-neurotoxins were recently discovered: contrary to κ-bungarotoxin or haditoxin, these are covalently bound where two molecules of α-cobratoxin are connected by two intermolecular disulfide bonds [35]. Before describing a biological activity of this new tool, it should be mentioned that such intermolecular disulfide is the first case of this post-translational modification found for the whole huge family of three-finger toxins. Dimeric α-cobratoxin retained, although at a lower level, the capacity to block α7 and muscle-type nAChRs and in addition acquired the ability to block α3β2 nAChR - again, with lower potency than did κ-bungarotoxin [35]. Interestingly, selective reduction of the disulfides in the loop II of dimeric α-cobratoxin abolished its activity against α7 nAChR. It could be expected in view of earlier described similar modification of α-cobratoxin itself, but this chemical modification even increased the affinity for α3β2 nAChR [36]. Since dimeric α-cobratoxin is present in the
As will be shown later, the main contribution to binding of α-neurotoxins both to nAChRs and to their models comes from the tip of the central loop II of α-neurotoxins. In dimeric α-cobratoxin the two tips are in close proximity and computer modeling showed impossibility of docking such a structure to AChBP, suggesting that some conformational changes should occur in the dimeric α-cobratoxin to ensure its binding observed in radioligand and electrophysiology experiments [36].
The discovery of dimeric α-cobratoxin was followed by finding another three-fingered toxin where monomers are connected by a disulfide bridge [37]. It was irditoxin isolated from Colubrid snake
3.3. Weak (non-conventional) three-fingered neurotoxins
A characteristic feature of this group of three-fingered toxins is the presence of additional disulfide bridge not in the central loop II, as in long-chain α-neurotoxins or in κ-bungarotoxins, but in the N- terminal loop I. Some representatives of this group were known long ago, but many of them did not have a strong toxicity (that is why their name was “weak toxins”) and their targets were unknown. At present this group of toxins, consisting of 62-68 amino acid residues, is quite well investigated and has a more general name “non-conventional neurotoxins” [38]. The toxicities for the most of group members are very low (5-80 mg/kg) in contrast to classical α-neurotoxin with toxicities in the range from 0.04 to 0.3 mg/kg. However, some very potent toxins (like γ-bungarotoxin with LD50 of 0.15 mg/kg) are also included in the group of non-conventional toxins. Since, as mentioned above, molecular targets of weak (non-conventional) toxins for a long time were unknown, an important step in this field was the work [39] where was discovered that weak toxin (WTX) from
3.4. Three-finger snake neurotoxins having other targets than nicotinic acetylcholine receptors
Before considering in detail the mechanisms of interactions between α-neurotoxins and nAChRs and describing their earlier and current roles of tools, it is appropriate to say a few words about the whole family of three-finger proteins from snake venoms (see reviews [16,17]). They all have the same “three-finger” fold but are decorated with quite different functionally active amino-acid residue and, as a result, attack distinct targets. For example, in the preceding paragraph we considered WTX from
Much more strong effects on muscarinic acetylcholine receptors exert so-called muscarinic neurotoxins isolated from the green mamba
There are also several three-finger proteins from snake venoms (calciceptin, FS2) blocking Ca2+ channels [47,48]. We should also mention here fasciculin, a three-finger protein with 4 disulfides, targeting the acetylcholinesterase. Interestingly, the X-ray structures of fasciculin in complex with acetylcholinesterases were the first examples presenting a three-finger toxin bound to its biological target [49,50].
One of the most well-represented groups in the snake venoms are so-called cytotoxins (some of them were earlier called cardiotoxins) which apparently do not have a single well-defined target but disrupt the cell membranes thus inducing a multitude of effects (see reviews [51,52]). As a result of proteomic studies new three-finger proteins are being found in the snake venoms, and one of the minor components in the
We also would like to mention here the recent discovery of three-finger neurotoxins which interact with another group of GPCR, namely with the adrenoreceptors [54,55]. These toxins are most similar to muscarinic toxins and were also isolated from the eastern green mamba
Although it is not the topic of the present review, it is appropriate to mention here that there are three-finger proteins in nervous and immune system of mammals and insects belonging to the Ly6 family and some of them bind to nicotinic acetylcholine receptors and regulate their functioning
3.5. Peptides from snake venoms acting on nicotinic acetylcholine receptors
Such peptides are not as numerous as α-neurotoxins or non-conventional toxins targeting different subtypes of nAChR. Until recently the only group was that of waglerins isolated from the venom of South Asian snake
A new peptide was recently found in the snake venom possessing a capacity to block muscle-type nAChR [71]. It is azemiopsin, isolated from the
4. α-Conotoxins, peptides from poisonous marine snails Conus , acting on nicotinic acetylcholine receptors
Historically, snake venom α-neurotoxins were the first extremely important tools which made possible “digging out” in a purified form the first representative of the nAChR family, namely the muscle-type receptor from the
Since this chapter is devoted to neurotoxic proteins and peptides interacting with nicotinic acetylcholine receptors, below we will consider only those conotoxins which target these receptors. The major group is α-conotoxins, competitive antagonists of nAChRs. They have 12-19 amino-acid residues, as a rule amidated C-terminus and two disulfide bonds between Cys residues C1–C3 and C2–C4 (see Table). There are also several other groups of conotoxins acting on nAChRs (ψ-, αA-, αAS-, αC-, αS- and αD), but they are not numerous, are not as widely used as α-conotoxins and will not be considered here.
|
|
|
|
3/5 α-conotoxins | |||
GI |
|
ECCNPACGRHYSC* | α1β1γ/εδ |
MI |
|
GRCCHPACGKNYSC* | α1β1γ/εδ |
SIA |
|
YCCHPACGKNFDC* | α1β1γ/εδ |
4/3 α- conotoxins | |||
ImI |
|
GCCSDPRCAWRC* | α7, α9α10; α3β2; α3β4 |
|
|
GCCSDPRCRYRCR | α9α10 |
4/4 α- conotoxins | |||
|
|
GCCSTPPCAVLYC* | α3(α6)β2, α3(α6)β4 |
4/6 α- conotoxins | |||
AuIB |
|
GCCSYPPCFATNPDC* | α3β4 |
4/7 α- conotoxins | |||
PnIA |
|
GCCSLPPCAANNPDYC* | α3β2 |
PnIВ |
|
GCCSLPPCALSNPDYC* | α7; α3β4 |
MII |
|
GCCSNPVCHLEHSNLC* | α3β2(β3); α6-containing |
|
|
GCCSDPRCNYDHPEIC* | α9α10; α3β4, α3(α5)β2 |
TxIA |
|
GCCSRPPCIANNPDLC* | α3β2 |
|
C. |
DECCSNPACRVNNPHVCRRR | α7, α6α3β2β3, α3β2 |
1 Scheme of disulfide closing for naturally-occurring α-conotoxins – |
|||
* indicates an amidated C-terminus; the names of α-conotoxins typed in italics mean that their structures were identified in cDNA libraries. |
α-Conotoxins are structurally subdivided into subgroups depending on the number of amino acid residues between the C2–C3 and C3–C4 cysteines (see Table) forming the first and second loops, respectively. This structural feature affects the α-conotoxin specificity to particular nAChR subtypes. All at present known 3/5 α-conotoxins are potent blockers of muscle type nAChRs (and conventionally can be called ‘muscle’ α-conotoxins). The members of other subgroups (4/3, 4/4, 4/6, 4/7) act on various neuronal nAChR subtypes (and can be called ‘neuronal’ α-conotoxins). It is very rare when naturally occurring neuronal α-conotoxin blocks specifically only one neuronal nAChR subtype, usually neuronal α-conotoxins interact with two or more nAChR subtypes (see Table).
Most of muscle 3/5 α-conotoxins can discriminate species-specifically two binding sites on muscle or
“Mutagenesis” studies of α-conotoxins (in fact not the mutagenesis as such, but substitutions of amino acid residues by solid-phase peptide synthesis) gave information about those residues which are the basis of the high affinity and selectivity to a particular receptor or receptor subgroup. For example, the crucial role of Arg9 in α-conotoxin GI, as well as of Pro6 and Tyr12 in α-conotoxin MI for discriminating the α1/γ- and α1/δ-sites was revealed [80-82]. Interestingly, Arg9 proved important for a neuronal 4/3 α-conotoxin RgIA for its α9α10 nAChR specificity [83]. Similar “mutagenesis” studies resulting in revelation of residues crucial for activity were done also for many other α-conotoxins (ImI, PnIA, MII, GID, Vc1.1, AuIB) [84-89].
Like in the analysis of interactions between different nAChR types and snake venom neurotoxins, when much efforts has been spent by many laboratories to establish the topography of their binding, similar studies have been undertaken to elucidate the mechanism of nAChR recognition by α-conotoxins. Among them were above-mentioned multiple substitutions in the amino acid sequences of naturally occurring α-conotoxins, making their structures more rigid, syntheses of radioactive, fluorescent and photoactivatable derivatives. Combination with mutagenesis of the receptor subunits (pair-wise mutagenesis) gave information about possible contact points between α-neurotoxins and nAChRs, as well as between α-conotoxins and nAChRs. The relevant information can be found in numerous reviews (see, for example, [90-92]), but will not be considered in detail here, because this chapter contains a special section where crystal structures of α-neurotoxins and α-conotoxins in complexes with the relevant biological targets will be discussed.
5. Three-dimensional structures of peptide and protein neurotoxins in complexes with the nicotinic receptor models and fragments
It was already mentioned that the crystal structure of the acetylcholine-binding protein (AChBP) provided an impressing jump in the structural analysis of not only nicotinic acetylcholine receptors but of all other members of the Cys-loop receptor family. This water-soluble protein was found to modulated synaptic transmission in glia of
Interestingly, the first AChBP crystal structure in complex with a competitive antagonist was that of
The comparison with the NMR and X-ray structures for α-neurotoxins revealed that α-cobratoxin did not need to change its conformation dramatically to be accommodated in the binding region of AChBP. On the contrary, the AChBP loop C containing the disulfide between the neighboring cysteines (which is also a characteristic feature of all nAChR α-subunits) had to move to periphery up to 10 Å from the position which it occupied in the AChBP containing no bound ligand. (This movement should be supplemented with essential changes in conformation of loop F from complementary AChBP protomer.) Moreover, the earlier solved structure of AChBP with such agonist as nicotine revealed that, when agonist comes to the binding site, loop C embraces it and moves closer to the central axis of the molecule [94]. At present there are many crystal structures of various AChBPs in complexes with versatile specific or nonselective agonists and antagonists of the muscle-type and neuronal nAChRs and it appears to be a general rule: antagonists versus agonists induce movements of the loop C in the opposite directions.
5.1. X-ray structure of the extracellular domain of muscle nAChR α1 subunit in complex with α-bungarotoxin
Until now we were considering the X-ray and Electron microscopy structures of closely related but independent objects of studies: acetylcholine binding proteins and
Although this domain is a monomer, its spatial structure is very similar to an AChBP protomer in a pentameric complex. A molecule of bound α-bungarotoxin occupies the position similar to that of α-cobratoxin in complex with
5.2. X-ray structure of α-bungarotoxin with a chimera of L. stagnalis AChBP/ligand-binding domain of the human α7 subunit
This work can be considered as a further development of the recent breakthrough in the analysis of ligand binding domains of nAChRs when an important step was done in ascending from models to true receptors. The authors of [107] managed to substitute about 70% of the amino-acid residues in
5.3. X-ray structure structures of AChBP complexes with α-conotoxins
The first X-ray structure of the AChBP complex with α-conotoxin [109] has been solved soon after elucidation of the X-ray structure of the
Hydrophobic contacts were found to play the major role in the interaction of α-conotoxin PnIA[A10L, D14K] with
Another interesting feature of AChBP complexes was for the first time observed with partial agonists: in distinct binding sites within a pentameric AChBP molecule these compounds had different orientations [96]. Such multiplicity was first thought to be inherent only in partial agonists, but later altering dispositions in the 5 AChBP binding sites were observed for the complexes of such alkaloid antagonists as strychnine and d-tubocurarine [113]. Moreover, in several binding sites two alkaloid molecules managed to be accommodated simultaneously [113].
Variations of the ligand orientation in the binding sites of AChBPs and nAChRs are of undoubted interest. In the
Indeed, interpretation of the cross-linking of photoactivatable derivative of α-conotoxin GI to
6. Summary
In this chapter we tried to briefly present almost a 50-year history of using protein and peptide neurotoxins in fundamental and practical studies of nicotinic acetylcholine receptors (nAChRs). It was shown that the discovery of α-neurotoxins in the snake venoms was an extremely important step which made possible identification and isolation in individual form of the first nAChR from the
Acknowledgments
The research was supported by RFBR grants and the grants of Presidium of RAS “Molecular and cellular biology” and ”Fundamental principles of medicine”.
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