Cysteine-rich secretory protein

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Crisp domain (CRD)
CRISP domains.png
The two domains of a Cysteine-rich secretory protein (CRISP). [1] CAP-like PR-1 domain in white. ShK-like CRD in red. Disulphides in yellow. Glycan chains not shown. ( PDB: 1WVR ​)
Identifiers
SymbolCrisp
Pfam PF08562
Pfam clan CL0213
InterPro IPR013871
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Cysteine-rich secretory proteins, often abbreviated as CRISPs, are a group of glycoproteins. [2] They are a subgroup of the CRISP, antigen 5 and Pr-1 (CAP) protein superfamily and also contain a domain related to the ShK toxins. [1] They are substantially implicated in the functioning of the mammalian reproductive system. [3] CRISPs are also found in a variety of snake venoms where they inhibit both smooth muscle contraction and cyclic nucleotide-gated ion channels. [4]

Contents

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). [1]

CRISPs are glycoproteins, with a number of carbohydrate glycans covalently attached to amino acid side-chains on their surface via glycosylation. [5] The primary structure is also rich in cysteine that form disulfide bonds, particularly in the hinge region and CRD. [1]

Mammalian reproduction

CRISPs are found in the testes and epididymis of mammals, and are also involved in the process of fertilisation. [2] In the spermatogenesis process (development of the spermatozoa in the testis), the CRISP2 protein is incorporated into the acrosome where it is believed to be involved in the adhesion of germ cells with Sertoli cells. CRISP2 also forms part of the 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, excreted from the prostate although its function is unknown. [3]

During capacitation, the penultimate stage of spermatozoa maturation, the acrosomal sperm head membrane is destabilised to allow greater binding between oocyte 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 activity, similar to the mechanism of action of the other major function of CRISPs in snake venom. [3] Research also suggests that CRISPs are involved in the oocyte-sperm binding needed for fertilisation. [2] Given the involvement of CRISPs in several stages of human reproduction, it is unsurprising that applications in treatment of infertility and as contraceptives are being actively investigated. [3]

Snake venom

The King Cobra (Ophiophagus hannah) for which the CRISP ophanin is named Ophiophagus hannah (2).jpg
The King Cobra ( Ophiophagus hannah ) for which the CRISP ophanin is named

CRISPs are found in the venom of a wide variety of snake species. [4] Examples include ablomin from the Japanese Mamushi snake ( Gloydius blomhoffii , formerly Agkistrodon blomhoffi), [6] latisemin from the Erabu sea snake ( Laticauda semifasciata ), [4] ophanin from the King Cobra ( Ophiophagus hannah ), [7] piscivorin from the Eastern Cottonmouth ( Agkistrodon piscivorus ) [7] and triflin from the Habu snake ( Trimeresurus flavoviridis ) [8] – 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 channels and also because they reduce potassium-induced smooth muscle contraction. [6] Among the four CRISPs isolated from the Monocled Cobra ( Naja kaouthia ) and the three from the Egyptian Cobra ( Naja haje ), ion channel activity occurred by blocking of cyclic nucleotide-gated ion channels. One of the N. haje CRISPs was the first example of an acidic 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. [9]

Related Research Articles

<span class="mw-page-title-main">Epididymis</span> Tube that connects a testicle to a vas deferens

The epididymis is an elongated tubular structure 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, 6 to 7 centimetres in length; uncoiled the tube would be approximately 6 m long. It connects the testicle to the vas deferens in the male reproductive system. The epididymis serves as an interconnection between the multiple efferent ducts at the rear of a testicle (proximally), and the vas deferens (distally). Its primary function is the storage, maturation and transport of sperm cells.

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. In vivo, capacitation occurs after ejaculation, when the spermatozoa leave the vagina and enter the upper female reproductive tract. The uterus aids in the steps of capacitation by secreting sterol-binding albumin, lipoproteins, and proteolytic and glycosidasic enzymes such as heparin.

Phospholipase A<sub>2</sub> Peripheral membrane protein

The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:

<span class="mw-page-title-main">Spermiogenesis</span> Final stage of spermatogenesis, involving spermatid maturation

Spermiogenesis is the final stage of spermatogenesis, during which the spermatids develop into mature spermatozoa. At the beginning of the stage, the spermatid is a more or less circular cell containing a nucleus, Golgi apparatus, centriole and mitochondria; by the end of the process, it has radically transformed into an elongated spermatozoon, complete with a head, midpiece, and tail.

Ophanin is a toxin found in the venom of the King Cobra, which lives throughout South East Asia. This toxin belongs to the cysteine-rich secretory protein (CRISP) family. Ophanin weakly blocks the contraction of smooth muscles elicited by high potassium-induced depolarization, suggesting that it inhibits voltage-dependent calcium channels.

<span class="mw-page-title-main">Disintegrin</span> Proteins from viper venom inhibiting platelets aggregation

Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion.

<span class="mw-page-title-main">Mamushi</span> Species of snake

Gloydius blomhoffii, commonly known as the mamushi, Japanese moccasin, Japanese pit viper, Qichun snake, Salmusa or Japanese mamushi, is a venomous pit viper species found in Japan. It was once considered to have 4 subspecies, but it is now considered monotypic.

<span class="mw-page-title-main">Calciseptine</span> Neurotoxin

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

<span class="mw-page-title-main">CRISP3</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich secretory protein 3 is a cysteine-rich secretory protein that in humans is encoded by the CRISP3 gene.

<span class="mw-page-title-main">CRISP1</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich secretory protein 1 is a cysteine-rich secretory protein that in humans is encoded by the CRISP1 gene.

<span class="mw-page-title-main">CRISP2</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich secretory protein 2 is a cysteine-rich secretory protein that in humans is encoded by the CRISP2 gene.

Phoneutria keyserlingi is a species of spiders in the family Ctenidae, found in Brazil.

<span class="mw-page-title-main">CatSper1</span> Protein-coding gene in the species Homo sapiens

CatSper1, is a protein which in humans is encoded by the CATSPER1 gene. CatSper1 is a member of the cation channels of sperm family of protein. The four proteins in this family together form a Ca2+-permeant ion channel specific essential for the correct function of sperm cells.

Ablomin is a toxin present in the venom of the Japanese Mamushi snake, which blocks L-type voltage-gated calcium channels.

Triflin is a cysteine-rich secretory protein (CRISP), which is excreted by the venom gland of the Habu snake. Triflin reduces high potassium-induced smooth muscle contraction, suggesting a blocking effect on L-type calcium channels.

Piscivorin is a component of snake venom secreted by the Eastern Cottonmouth. It is a member of the cysteine-rich secretory protein (CRISP) family, which blocks voltage-dependent calcium channels.

Latisemin is a cysteine-rich secretory protein that can be isolated from the venom of the Black-banded sea krait, a sea snake indigenous to the warmer waters of the western Pacific Ocean. It is a toxin that inhibits cyclic nucleotide-gated ion channels and blocks L-type calcium channels, thereby reducing smooth muscle contraction.

<span class="mw-page-title-main">ADAM7</span> Protein-coding gene in the species Homo sapiens

Disintegrin and metalloproteinase domain-containing protein 7 is a protein that in humans is encoded by the ADAM7 gene. ADAM7 is an 85-kDa enzyme that is a member of the transmembrane ADAM protein family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. ADAM7 is important for the maturation of sperm cells in mammals. ADAM7 is also denoted as: ADAM_7, ADAM-7, EAPI, GP-83, and GP83.

<span class="mw-page-title-main">Cysteine-rich secretory protein superfamily</span>

The CAP superfamily is a large superfamily of secreted proteins that are produced by a wide range of organisms, including prokaryotes and non-vertebrate eukaryotes.

Atrolysin A is an enzyme that is one of six hemorrhagic toxins found in the venom of western diamondback rattlesnake. This endopeptidase has a length of 419 amino acid residues. The metalloproteinase disintegrin-like domain and the cysteine-rich domain of the enzyme are responsible for the enzyme's hemorrhagic effects on organisms via inhibition of platelet aggregation.

References

  1. 1 2 3 4 Guo M, Teng M, Niu L, Liu Q, Huang Q, Hao Q (April 2005). "Crystal structure of the cysteine-rich secretory protein stecrisp reveals that the cysteine-rich domain has a K+ channel inhibitor-like fold". The Journal of Biological Chemistry. 280 (13): 12405–12. doi: 10.1074/jbc.M413566200 . PMID   15596436.
  2. 1 2 3 Cammack R, Attwood TK, Campbell PN, Parish JH, Smith AD, Stirling JL, Vella F, eds. (2006). Oxford Dictionary of Biochemistry and Molecular Biology (2nd ed.). New York: Oxford University Press. p. 150. ISBN   0-19-852917-1 . Retrieved October 27, 2010.
  3. 1 2 3 4 Koppers AJ, Reddy T, O'Bryan MK (January 2011). "The role of cysteine-rich secretory proteins in male fertility". Asian Journal of Andrology. 13 (1): 111–7. doi:10.1038/aja.2010.77. PMC   3739402 . PMID   20972450.
  4. 1 2 3 Yamazaki Y, Morita T (September 2004). "Structure and function of snake venom cysteine-rich secretory proteins". Toxicon. 44 (3): 227–31. doi:10.1016/j.toxicon.2004.05.023. PMID   15302528.
  5. ↑ Cammack R, Attwood TK, Campbell PN, Parish JH, Smith AD, Stirling JL, Vella F, eds. (2006). Oxford Dictionary of Biochemistry and Molecular Biology (2nd ed.). New York: Oxford University Press. p. 286. ISBN   0-19-852917-1 . Retrieved October 28, 2010.
  6. 1 2 Yamazaki Y, Koike H, Sugiyama Y, Motoyoshi K, Wada T, Hishinuma S, Mita M, Morita T (June 2002). "Cloning and characterization of novel snake venom proteins that block smooth muscle contraction". European Journal of Biochemistry. 269 (11): 2708–15. doi: 10.1046/j.1432-1033.2002.02940.x . PMID   12047379.
  7. 1 2 Yamazaki Y, Hyodo F, Morita T (April 2003). "Wide distribution of cysteine-rich secretory proteins in snake venoms: isolation and cloning of novel snake venom cysteine-rich secretory proteins". Archives of Biochemistry and Biophysics. 412 (1): 133–41. doi:10.1016/S0003-9861(03)00028-6. PMID   12646276.
  8. ↑ Shikamoto Y, Suto K, Yamazaki Y, Morita T, Mizuno H (July 2005). "Crystal structure of a CRISP family Ca2+ -channel blocker derived from snake venom". Journal of Molecular Biology. 350 (4): 735–43. doi:10.1016/j.jmb.2005.05.020. PMID   15953617.
  9. ↑ Osipov AV, Levashov MY, Tsetlin VI, Utkin YN (March 2005). "Cobra venom contains a pool of cysteine-rich secretory proteins". Biochemical and Biophysical Research Communications. 328 (1): 177–82. doi:10.1016/j.bbrc.2004.12.154. PMID   15670767.
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