Cysteine-rich secretory proteins, often abbreviated as CRISPs, are a group of

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

s. They are a subgroup of the CRISP, antigen 5 and Pr-1 (

CAP A cap is a flat headgear, usually with a visor. Caps have crowns that fit very close to the head. They made their first appearance as early as 3200 BC. The origin of the word "cap" comes from the Old French word "chapeau" which means "head co ...

)

protein superfamily A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology (biology), homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if n ...

and also contain a domain related to the ShK toxins. They are substantially implicated in the functioning of the

mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...

ian reproductive system. CRISPs are also found in a variety of

snake venom Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is usually injected by unique fangs during a Snakebite, bite, though ...

s where they inhibit both smooth muscle contraction and

cyclic nucleotide-gated ion channel Cycle, cycles, or cyclic may refer to: Anthropology and social sciences * Cyclic history, a theory of history * Cyclical theory, a theory of American political history associated with Arthur Schlesinger, Sr. * Social cycle, various cycles in ...

Structure

CRISPs contain two domains joined by a hinge region. The larger domain is a CAP-like 'Pathogenesis-related 1' domain (PR-1), followed by the smaller ShK-like 'Cysteine-Rich Domain' (CRD). CRISPs are

s, with a number of

carbohydrate A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...

glycan The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate ...

covalently A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

attached to amino acid side-chains on their surface via

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

. The

primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

is also rich in

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

that form

disulfide bond In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inor ...

s, particularly in the hinge region and CRD.

Mammalian reproduction

CRISPs are found in the

testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...

and

epididymis The epididymis (; : epididymides or ) is an elongated tubular genital organ attached to the posterior side of each one of the two male reproductive glands, the testicles. It is a single, narrow, tightly coiled tube in adult humans, in length; ...

of mammals, and are also involved in the process of

fertilisation Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a zygote and initiate its development into a new individual organism or of ...

. In the

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the Mitosis, mitotic division of the stem cells located close to the basement membrane of ...

process (development of the

spermatozoa A spermatozoon (; also spelled spermatozoön; : spermatozoa; ) is a motile sperm cell (biology), cell produced by male animals relying on internal fertilization. A spermatozoon is a moving form of the ploidy, haploid cell (biology), cell that is ...

in the

testis A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is Homology (biology), homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of Androgen, androgens, p ...

), the CRISP2

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

is incorporated into the

acrosome The acrosome is an organelle that develops over the anterior (front) half of the head in the spermatozoa (sperm cells) of humans and many other animals. It is a cap-like structure derived from the Golgi apparatus. In placental mammals, the acroso ...

where it is believed to be involved in the

adhesion Adhesion is the tendency of dissimilar particles or interface (matter), surfaces to cling to one another. (Cohesion (chemistry), Cohesion refers to the tendency of similar or identical particles and surfaces to cling to one another.) The ...

germ cell A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they unde ...

s with

Sertoli cell Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-sti ...

s. CRISP2 also forms part of the

sperm Sperm (: sperm or sperms) is the male reproductive Cell (biology), cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm ...

tail where it is thought to be involved in regulating flagellar beating. Proteins CRISP1 and CRISP4 are both found in the epididymis where they are also incorporated within the spermatozoa as it matures. Protein CRISP3 is found in

seminal fluid Semen, also known as seminal fluid, is a bodily fluid that contains spermatozoa which is secreted by the male gonads (sexual glands) and other sexual organs of male or hermaphroditic animals. In humans and placental mammals, seminal fluid i ...

, excreted from the

prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...

although its function is unknown. During

capacitation Capacitation is the penultimate step in the maturation of mammalian spermatozoa and is required to render them competent to fertilize an oocyte. This step is a biochemical event; the sperm move normally and look mature prior to capacitation. ''I ...

, the penultimate stage of spermatozoa maturation, the acrosomal sperm head membrane is destabilised to allow greater binding between

oocyte An oocyte (, oöcyte, or ovocyte) is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ger ...

and sperm. CRISP1 binds to surface of the sperm leading to a quiescent state of storage prior to capacitation. The mechanism is believed to involve inhibition of

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

activity, similar to the mechanism of action of the other major function of CRISPs in

. Research also suggests that CRISPs are involved in the oocyte-sperm binding needed for fertilisation. Given the involvement of CRISPs in several stages of

human reproduction Human sexual reproduction, to produce offspring, begins with fertilization. Successful reproduction typically involves sexual intercourse between a healthy, sexually mature and fertile male and female. During sexual intercourse, sperm cells are ...

, it is unsurprising that applications in treatment of

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

and as

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...

s are being actively investigated.

Snake venom

CRISPs are found in the

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

of a wide variety of

snake Snakes are elongated limbless reptiles of the suborder Serpentes (). Cladistically squamates, snakes are ectothermic, amniote vertebrates covered in overlapping scales much like other members of the group. Many species of snakes have s ...

species. Examples include ablomin from the Japanese

Mamushi ''Gloydius blomhoffii'', commonly known as the mamushi,Mehrtens JM (1987). ''Living Snakes of the World in Color''. New York: Sterling Publishers. 480 pp. . Japanese moccasin, Japanese pit viper, Qichun snake, Salmusa or Japanese mamushi,Gumprec ...

snake (''

Gloydius blomhoffii ''Gloydius blomhoffii'', commonly known as the mamushi,Mehrtens JM (1987). ''Living Snakes of the World in Color''. New York: Sterling Publishers. 480 pp. . Japanese moccasin, Japanese pit viper, Qichun snake, Salmusa or Japanese mamushi,Gumprec ...

'', formerly ''

Agkistrodon ''Agkistrodon'' is a genus of pit vipers commonly known as American moccasins.Crother, B. I. (ed.). 2017. ''Scientific and Standard English Names of Amphibians and Reptiles of North America North of Mexico, with Comments Regarding Confidence in ...

blomhoffi''), latisemin from the Erabu sea snake (''

Laticauda semifasciata The black-banded sea krait (''Laticauda semifasciata''), also known Common name, commonly as the Chinese sea snake or erabu, is a largely amphibious species of extremely venomous snake, venomous marine reptile in the subfamily Laticaudinae, Famil ...

''), ophanin from the King Cobra (''

Ophiophagus hannah The king cobra (''Ophiophagus hannah'') is a species complex of snakes endemic to Asia. With an average of and a record length of , it is the world's longest venomous snake and among the heaviest. Under the genus ''Ophiophagus'', it is not p ...

''), piscivorin from the Eastern Cottonmouth (''

Agkistrodon piscivorus ''Agkistrodon piscivorus'' is a species of venomous snake, a pit viper in the subfamily Crotalinae of the family Viperidae. It is one of the world's few semiaquatic vipers (along with the Florida cottonmouth), and is native to the Southeaster ...

'') and triflin from the Habu snake (''

Trimeresurus flavoviridis The Okinawa habuU.S. Navy (1991). ''Poisonous Snakes of the World''. New York: US Government / Dover Publications Inc. 203 pp. . (''Protobothrops flavoviridis'') is a species of pit viper endemic to the Ryukyu Islands of Japan. No subspecies are ...

'') – each of these proteins is named for the snake species in which it was discovered. These venoms are toxic due to their blocking of

calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, which are a type of calcium channel regulated by changes in membrane potential. Some calcium chan ...

s and also because they reduce potassium-induced smooth muscle contraction. Among the four CRISPs isolated from the Monocled Cobra (''

Naja kaouthia The monocled cobra (''Naja kaouthia''), also called monocellate cobra and Indian spitting cobra, is a venomous cobra species widespread across South and Southeast Asia. It is characterized by a distinctive circular or "monocle"-shaped marking on ...

'') and the three from the Egyptian Cobra ('' Naja haje''), ion channel activity occurred by blocking of

s. One of the ''N. haje'' CRISPs was the first example of an

acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...

ic CRISP in reptilian venom. The selective ion channel activity of snake CRISPs, coupled with the variety of CRISPs available as the pool of venom proteins appears highly variable between (at least) cobra species, provide a valuable tool for probing the mechanisms of ion channel activity.

References

{{Reflist, 32em Glycoproteins Cysteine-rich proteins