Abstract
This review on all spider venom components known by the end of 2010 bases on 1618 records for
venom compounds from 174 spider species (= 0.41% of all known species) belonging to 32 families
(= 29% of all existing spider families). Spiders investigated for venom research are either big (many
mygalomorph species, Nephilidae, Ctenidae and Sparassidae) or medically important for humans
(e.g. Loxosceles or Latrodectus species). Venom research widely ignored so far the two most speciesrich families (Salticidae and Linyphiidae) and strongly neglected several other very abundant families
(Araneidae, Lycosidae, Theridiidae, Thomisidae and Gnaphosidae).
We grouped the known 1618 records for venom compounds into six categories: low molecular mass
compounds (16 % of all compounds), acylpolyamines (11 %), linear peptides (6 %), cysteine-knotted
mini-proteins (60 %), neurotoxic proteins (1 %) and enzymes (6 %). Low molecular mass compounds
are known from many spider families and contain organic acids, nucleosides, nucleotides, amino
acids, amines, polyamines, and some further substances, many of them acting as neurotransmitters.
Acylpolyamines contain amino acids (Araneidae and Nephilidae) or not (several other families) and
show a very high diversity within one species. Linear peptides, also called cytolytic, membranolytic or
antimicrobial, exert a highly specific structure and are so far only known from Ctenidae, Lycosidae,
Oxyopidae and Zodariidae. Cysteine-knotted mini-proteins represent the majority of venom
compounds because research so far focused on them. They probably occur in most but not all spider
families. Neurotoxic proteins so far are only known from theridiid spiders. Enzymes had been
neglected for some time but meanwhile it becomes obvious that they play an important role in
spider venoms. Sixteen enzymes either cleave polymers in the extracellular matrix or target
phospholipids and related compounds in membranes.
The overall structure of these compounds is given and the function, as far as it is known, is
described. Since several of these component groups are presented in one average spider venom, we
discuss the known interactions and synergisms and give reasons for such a functional redundancy.
We also discuss main evolutionary pathways for spider venom compounds such as high variability
among components of one group, synergistic interactions between cysteine-knotted mini-proteins
and other components (low molecular mass compounds and linear peptides), change of function
from ion-channel acting mini-proteins to cytolytic effects and replacement of mini-proteins by linear
peptides, acylpolyamines, large proteins or enzymes. We also add first phylogenetic considerations.
Introduction
Spiders are after insects the most diverse terrestrial organism group and they comprise currently
42,055 species made available as an Internet database by Platnick (2011). Spiders evolved over some
300 million years, exert several characteristics and their unique combination is the reason for the
unrivalled evolutionary success story of this group. (1) As hydraulic arachnids, spiders only possess
flexor muscles in their limbs. Instead of extensor muscles, the hydraulic pressure of their hemolymph
is fine-tuned by a well-balanced system of valves, which provides the necessary back-pressure. Since
the long tubes of spider legs need only one system of muscles, spiders use the available space to
enlarge their flexors, thus their muscles are relatively thicker than in comparable arthropods making
spiders in general more powerful than insects (Shultz, 1991). (2) The distal end of the male pedipalp
developed into a complex structure composed of fixed and movable sclerites that are used to
transfer sperm to the female seminal receptacles during mating. These sclerites enable the males to
perform safe sperm transfer, but also to lock this secondary sexual organ to the female genital
opening, thus preventing mating outside the own species. This safe mode (key-lock-mechanism) is
considered as major driver for a fast species radiation (Foelix, 2011). (3) Spiders possess up to six
different silk gland types that allow them to use silk for a variety of needs. Spider silk is a polymer
protein fiber with remarkable material properties, making it one of the most resistant and elastic
biomaterials. Spiders developed various web types to capture prey items, they also wrap them with
silk until they are defenceless, and they build silken retreats, cocoons and draglines. This makes
spiders superior predators and there is presently only one spider species known feeding
predominantly on plant material (Meehan et al., 2009). (4) Spiders possess one pair of venom glands
in the basal segment of the chelicerae (mygalomorph spiders) or in their prosoma (araneomorph
spiders), and they inject small venom quantities into a prey item or predator to paralyze and/or kill
and/or harm and/or possibly also to pre-digest it. Spider venom is a complex mixture of hundreds of
components, mainly but not exclusively consisting of peptides and proteins, acting on myriad
different targets in the prey organism. These targets include among others the extracellular matrix,
membranes and a variety of receptors, quite often located in the nervous or muscular system.
The venom glands of spiders are already present in the oldest spider group, the Mesothelae, but
they are very small. The cylindrical gland lies in the anterior portion of the cheliceral basal segment
and a thin duct leads to an opening at the inner side of the fang, relatively distant from the tip of the
fang (Foelix and Erb, 2010). Considering size and cheliceral power it may be doubtful how effectively
the venom supports the predation success of these spiders. In mygalomorph spiders, the situation
becomes clear. The well-developed venom glands, still in the basal cheliceral segment, produce
powerful venom that is injected via the cheliceral fangs into the prey. The openings of the venom
ducts lie at the convex side of the fang and can easily be seen if viewed from the ventral side. In all
other spiders (Araneomorphae), the openings of the venom ducts are rather large and situated on
the concave side of the cheliceral fangs, close to the tip. Moreover, the venom glands become much
larger and reach into the prosoma where they can take a considerable proportion of this body part
(Fig. 1; Foelix, 2011).
Though the possession of venom and venom glands is one of the key features of the success story of
spiders, two or three spider families secondarily reduced their venom glands. (1) Uloboridae are
small to medium-sized spiders producing cribellate silk. They lost their venom glands because
uloborids evolved a unique technique to compact the living prey with extensive wrapping and by
wetting the entire prey package with a powerful fluid that kills insects very fast. This fluid contains
aggressive digestive enzymes dissolving the insect's intersegmental membranes and inner tissue, but
it could also contain toxins (Weng et al., 2006). (2) The only two species in the single
genus Holarchaea of the family Holarchaeiidae, minute spiders from the moss and litter layer of the
New Zealand wet rain forest, have very long and slender cheliceral fangs without a venom gland
opening on the cheliceral tip, and Forster and Platnick (1977) concluded that these highly modified
spiders reduced their venom glands. (3) Symphytognathidae is another small family of tiny spiders,
comprising about 65 species, characterized by chelicerae fused at least at their base. This raises
doubts about the functionality of the chelicerae and it had widely been assumed that
symphytognathids lost their venom glands. However, in a taxonomic review Forster and Platnick
(1977) described that the fangs bear an opening on their retrolateral side that presumably leads to a
poison gland. No venom gland loss but a complete change of function happened in spitting spiders
(Scytodes, Scytodidae family, 228 species) that highly modified their venom glands to produce a
gluey fibrous glycoprotein. This substance is spit from a distance of 2 cm well-directed onto the
victim to fix it to the ground (Kovoor, 1987).
Even if the prey subduing process is much easier and safer for a spider when it can use its powerful
venom, spiders do not exclusively rely on the use of their venom. The chelicerae of spiders are a
strong tool to overwhelm a prey animal, and spiders routinely size and chew small arthropods
without applying any venom. It is basically a question of the size ratio between predator and prey
that determines the predator's decision: very small and/or defenceless arthropods are easily picked
up and crashed with the chelicerae, while larger, dangerous or well-defended items are much more
carefully approached and only attacked with venom injection. If the spider comes to the decision
that the target is too large or dangerous, it will not attack and even get away.
Within the evolution of spiders the manageable size ratio of predators to prey has been considerably
modified during several parallel processes. Most mygalomorph spiders are large animals; all have an
orthognath chelicerae position and a relatively small venom gland compared to the body. The venom
glands are restricted in size by the basal cheliceral segment, where muscles and venom glands
compete for space. This limits the possibility to prey on large animals and mygalomorphs could only
try to escape from this dilemma by becoming bigger, increasing the toxicity of their venom, or by
constructing silken webs. The first two possibilities have been used up to some success but more or
less functional webs can only be built by smaller species and are common only in a few mygalomorph
groups (e.g. diplurids). The next most important evolutionary step was the change to a labidognath
cheliceral position achieved by araneomorph spiders. This step was so successful that today more
than 93% of all spider species are labidognath (Platnick, 2011). The modified cheliceral position does
not need the big muscle packages of orthognath spiders; thus chelicerae could become smaller
allowing parallel reduction of the body size. At the same time, the venom gland moved into the
prosoma where it could enlarge its volume without conflicting too much with other organ systems
(Fig. 1). These combinations allowed spiders to reduce their body size considerably, and today most
spiders are small creatures with the most frequent body length size classes between 1 and 10 mm.
Within araneomorph spiders, sometimes also called “true” spiders, several lineages of webs evolved.
Important achievements were the enlargement of webs into the third dimension (funnel webs, sheet
webs, orb webs and many more types), regular and even geometrical arrangements of silken threats
to reduce the amount of silk needed (up to orb webs that need only three attachment points and
several other types of two-dimensional webs), the invention of cribellate silk or sticky glue to adhere
entangled insects, thus preventing escape and reducing the need of a spider's immediate
intervention (automated traps) and social mode of living with group-attacks on large prey items
(Nentwig, 1985). These achievements, often combined, enable araneomorph spiders to predate on
relatively large prey targets of all invertebrate groups (Nentwig and Wissel, 1986). Nevertheless, also
labidognath spiders that do not build webs are very successful, and today some 50–55% of all
labidognath spiders do not build webs while 45–50% are web-builders.
The natural prey of spiders consists predominantly of invertebrates, mainly insects. Among other
arthropods, conspecific and non-conspecific spiders are a frequent part of a spider's diet. Further
arthropod prey groups comprise opilionids and mites, uncommonly also millipedes and crustaceans
(isopods). Among the non-arthropod invertebrates, occasionally annelid worms and slugs are eaten
by spiders (Nentwig, 1987). Large spiders are also able to catch small vertebrates: Pisaurids are
frequently successful in predating on small amphibians and small fish; mygalomorphs get
occasionally small rodents and also birds, primarily small and helpless specimens such as nestlings;
sparassids have casually been observed preying on small lizards.
Spiders are usually polyphagous, this means they are not specialised on a given prey type or taxon.
Nevertheless, several cases of nutritional specialization among spiders are known. Bola spiders
(Mastophora or Celaenia among Araneidae) lure their prey with the sex pheromone of noctuid
moths and catch exclusively these moths (Gemeno et al., 2000). Some mimetid genera
(Ero, Mimetus and probably several more) are specialised web spider predators and developed
complex behavioural tasks to overwhelm the resident web spider. Zodarion species and
aphantochilid spiders are usually regarded as obligate myrmecophagous (Pekar et al., 2007) and also
in Theridiidae, Salticidae, Clubionidae and Gnaphosidae some genera specialized on ants. Spiders of
the South African genus Ammoxenus (Ammoxenidae) are described as termite feeders (Dippenaar
and Meyer, 1980). These records amount to roughly 2% of all known spider species that are
specialized (i.e. more or less monophagous), while 98% are not.
From these considerations it can be concluded that the venom of spiders predominantly is not
specific to a given invertebrate or insect group but rather unspecialized to be effective towards the
broad spectrum of prey spiders naturally encountered. It is possible that the venom of the above
listed monophagous spiders is more tailored towards their specific prey taxon but from none of the
mentioned taxa venom has been investigated to date. Following the same line of argumentation, also
vertebrates, including humans, are no important target of spiders and their venom. Nevertheless
spider toxins are active against mammals including humans. One may hypothesize that the same
mode of action is also effective or the same receptors/targets are also present in invertebrates and
vertebrates or that the venom is complex enough to target a broad range of living organisms that
may also be predators.
The effect of spider bites and spider venom on humans has largely been overestimated. Most spiders
have only tiny mouthparts and short fangs, thus only large spiders can penetrate the strong human
skin. Moreover, a specific aggressive behaviour or adaptation to the human environment is needed
and there is consensus that only a limited number of taxa can seriously bite and harm humans. These
spiders include several mygalomorph taxa (e.g. Atrax and Hadronyche) and the araneomorph
genera Phoneutria, Loxosceles and Latrodectus, comprising altogether less than 100 species. The
medical differential diagnosis of spider bites is usually performed not very professionally and
includes other arthropod bites, skin infections, and exposure to chemical or physical agents. In total,
there are about 100 reliably reported deaths from spider bites in the twentieth century, leaving
spiders as mortality source of humans far behind bees and wasps or scorpions (Diaz, 2004, Isbister
and Gray, 2002).
One of the strongest motivations to investigate spider venoms derives from this human
argumentation. On the one hand spider venoms are of limited danger to humans, which justifies
research into therapeutic means. On the other hand, spider venoms are seen as rich source of often
highly specialized toxins, addressing selected receptors at muscles and nerve cells, also in
vertebrates. This “library” or “peptide treasure” or “natural goldmine” of bioactives is being
intensively investigated for scientific, medical and pharmaceutical reasons because some spider
toxins proved to block highly specifically receptors playing a key role in important human
physiological processes. There are recent reviews with a focus on pharmacological aspects of spider
venoms (Corzo and Escoubas, 2003, Escoubas and Rash, 2004, Escoubas et al., 2000b, Rash and
Hodgson, 2002), on the importance of venom components as leads for new drugs (Bosmans et al.,
2009, Escoubas and King, 2009, Estrada et al., 2007, Favreau et al., 2001, Stöcklin and Favreau, 2002,
Stöcklin and Vorherr, 2010), and, more generally, on biosynthesis, structure and function of venom
compounds (Vassilevski et al., 2009). Understanding the venomous function, how genes regulate
such a complex machinery from chromosomes to venom gland to venom and what mechanisms are
involved in the fast evolutionary process of venom components is also a major field of investigation
(Ménez et al., 2006).
With this review we provide a comprehensive and recent overview on the current diversity of venom
compounds and relate it to the diversity of spiders. We have voluntarily decided to structure this
review around structural patterns of venom components, using the mini-protein toxins (the largest
family of spider toxins made of peptides strongly folded by disulphide bonds) as central element. We
benefit from the progress in venom research of the recent years that included further spider species,
thus enlarging our still limited knowledge basis a bit. We aim at providing a holistic view of the spider
venom machinery as a concept, which not only enabled a spider to paralyze very efficiently most (if
not all) potential prey items over time and adapt to predators and environmental changes, but which
had also been modified and restructured several times within the evolution of these fascinating
animals.