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Review
.2008:(184):171-206.
doi: 10.1007/978-3-540-74805-2_7.

alpha-Latrotoxin and its receptors

Affiliations
Review

alpha-Latrotoxin and its receptors

Yuri A Ushkaryov et al. Handb Exp Pharmacol.2008.

Abstract

alpha-Latrotoxin (alpha-LTX) from black widow spider venom induces exhaustive release of neurotransmitters from vertebrate nerve terminals and endocrine cells. This 130-kDa protein has been employed for many years as a molecular tool to study exocytosis. However, its action is complex: in neurons, alpha-LTX induces massive secretion both in the presence of extracellular Ca(2+) (Ca(2+) (e)) and in its absence; in endocrine cells, it usually requires Ca(2+) (e). To use this toxin for further dissection of secretory mechanisms, one needs an in-depth understanding of its functions. One such function that explains some alpha-LTX effects is its ability to form cation-permeable channels in artificial lipid bilayers. The mechanism of alpha-LTX pore formation, revealed by cryo-electron microscopy, involves toxin assembly into homotetrameric complexes which harbor a central channel and can insert into lipid membranes. However, in biological membranes, alpha-LTX cannot exert its actions without binding to specific receptors of the plasma membrane. Three proteins with distinct structures have been found to bind alpha-LTX: neurexin Ialpha, latrophilin 1, and receptor-like protein tyrosine phosphatase sigma. Upon binding a receptor, alpha-LTX forms channels permeable to cations and small molecules; the toxin may also activate the receptor. To distinguish between the pore- and receptor-mediated effects, and to study structure-function relationships in the toxin, alpha-LTX mutants have been used.

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Figures

Figure 1
Figure 1
The structure of α-LTX. A, Schematic of α-LTX processing in the venom gland. B, Primary and domain structure. The numbered boxes, ankyrin repeats (ARs). Grey, imperfect repeats; C, conserved cysteines residues in the N-terminal domain; open arrowhead, insert in the mutant α-LTXN4C. Protein domains identified from the 3D structure (Orlova et al. 2000) are delimited below. C, 3D reconstructions of the α-LTX monomer, dimer and tetramer, viewed from the top and side. The monomer has been computationally extracted from the experimentally determined tetramer structure. Leftmost image, a scheme of the monomer, with the domains designated by different shades of grey. Filled arrowhead, strong association of the head domains in the dimer.
Figure 2
Figure 2
Membrane topography of the α-LTX pore. Cross-section of the α-LTX tetramer embedded in a membrane (as observed in liposomes) (Orlova et al. 2000) is shown alongside the cut-open voltage-dependent K+ channel (Kv1.2) (Long et al. 2005) and Ca2+ release channel (ryanodine receptor) (Serysheva et al. 2005). Fully hydrated cations and molecules known to permeate through the respective channels are shown next to each reconstruction (FITC, fluoresceine isothiocyanate; NE, norepinephrine). The narrowest part of the α-LTX channel is 10 Å. Molecular images were produced using the UCSF Chimera package (Pettersen et al. 2004).
Figure 3
Figure 3
Generalised structure and functions of neurexins. A, Domain structure of α- and β-neurexins. Scale above shows amino acid positions. Arrowheads, splice site 4; SP, signal peptide; LNS, laminin G/NRX/sex hormone-binding globulin-like domains; EGF, epidermal growth factor-like repeats; CH, O-linked carbohydrate attachment domain; bracket, α-LTX binding site. α- and β-NRXs are identical to the right of the dotted line. B, Scheme of NRX interactions. Domain names: CaMK, Ca2+, calmodulin-dependent protein kinase homology; CI, CaMK-interacting; GuK, membrane-associated pseudo-guanylate kinase; MI, munc18-interacting; VI, Veli (vertebrateLin7)-interacting. Other abbreviations: 4.1, protein 4.1 bound to actin; Mint, munc18-interacting protein; NT, neurotransmitter; PTB, phosphotyrosine binding; SH3, src homology; S-SCAM, synaptic scaffolding molecule; SV, synaptic vesicle; VDCC, voltage-dependent Ca2+-channel. Dotted arrows, protein interactions; solid arrows, formation of the SNARE complex involved in exocytosis of synaptic vesicles.
Figure 4
Figure 4
LPH structure and processing. A, Generalised domain structure of latrophilins. 7TMRs, seven transmembrane regions and corresponding loops; arrow, cleavage point; bracket, the site of α-LTX binding in LPH1; GBL, galactose-binding lectin; GPS, GPCR-proteolysis site domain; HRM, hormone receptor motif; STP, Ser-, Thr- and Pro-rich domain. B. Scheme of LPH processing and functioning (Volynski et al. 2004). See text for details. ER, endoplasmic reticulum.
Figure 5
Figure 5
PTPσ structure and functions. A. Generalised domain structure of receptor-like PTPσ. FN3, fibronectin type III-homology domains; Ig, immunoglobulin-like domains; PTPc, catalytic PTP domain; PTPase, pseudo-phosphatase domain. Arrow, proteolytic cleavage site; bracket, α-LTX binding site. B, Cellular functions and interactions of PTPσ. Ligand binding leads to dimerisation and inhibition of the intracellular domains. PTPσ interaction with EGFR activates the ERK-mediated signalling and upregulates the TACE metalloprotease which cleaves the P subunit and releases E subunit. PTPσ may interact with HSPG of the basement membrane and nucleolin on muscle cells. PTPσ binds N-cadherin and dephosphorylates it, causing increased adhesion and inhibition of axonal growth. In mice lacking PTPσ, N-cadherin is hyper-phosphorylated; this reduces adhesion and increases neuronal growth. EGFR, epidermic growth factor receptor; ERKs, MAP kinases ERK1 and ERK2; HSPG, heparin sulphate proteoglycan; cat, catenin.
Figure 6
Figure 6
Diverse mechanisms of α-LTX action.Right, Ca2+ is present in the medium. The pathways shown are described in the text. CC; Ca2+ channels; DAG, diacyl glycerol; LTX 4x, α-LTX tetramers; MC, mitochondria.Left, Ca2+-free conditions. For main comments, see text. The possible pathways for Ca2+-independent exocytosis shown include: (1) high concentrations of Na+ mimicking Ca2+; (2) the internalised domains of α-LTX interacting with components of the exocytotic machinery (E); (3) α-LTX exerting direct fusogenic action.
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