A ribosome-inactivating protein (RIP) is a
protein synthesis inhibitor that acts at the
eukaryoticribosome.[2] This
protein family describes a large family of such proteins that work by acting as
rRNA N-glycosylase (EC 3.2.2.22). They inactivate 60S ribosomal subunits by an N-glycosidic cleavage, which releases a specific
adenine base from the sugar-phosphate backbone of 28S
rRNA.[3][4][5] RIPs exist in bacteria and plants.[6]
Members of the family include
shiga toxins, and type I (e.g.
trichosanthin and
luffin) and type II (e.g.
ricin,
agglutinin, and
abrin) ribosome inactivating proteins (RIPs). All these toxins are structurally related. RIPs have been of considerable interest because of their potential use, conjugated with monoclonal antibodies, as
immunotoxins to treat
cancers. Further,
trichosanthin has been shown to have potent activity against
HIV-1-infected
T cells and
macrophages.[7] Elucidation of the structure-function relationships of RIPs has therefore become a major research effort. It is now known that RIPs are structurally related. A conserved glutamic residue has been implicated in the catalytic mechanism;[8] this lies near a conserved arginine, which also plays a role in catalysis.[9]
Only a minority of RIPs are toxic to humans when consumed, and proteins of this family are found in the vast majority of plants used for human consumption, such as Rice, Maize and Barley. In plants, they are thought to defend against pathogens and insects.[10]
Ribosome-inactivating proteins (RIPs) are separated into the following types based on protein domain composition:[11]
Type I (A): RIPs-I are polypeptides composed of an A domain. This is the site of N-glycosidase activity.
Type II (AB): RIPs-II are composed of an A domain with similar catalytic activity to Type I RIPs, and a B domain with carbohydrate-binding (lectin) properties. The B domain is able to bind galactosyl moieties on the cell surface which facilitates entry into the cell, thus making Type II particularly cytotoxic. The A and B domains are fused together by disulfide bonds.[11][12] This group excludes bacterial
AB5 toxins such as Shiga toxin, as the carbohydrate-binding ability evolved separately and these toxins are more similar to type I RIPs.[11]
Type III: RIPs-III are separated into two subgroups. One subgroup (AC) contains the same original RIP domain (A), and a C-terminal with unknown functionality. The other subgroup (AD) is similar to Type I, but contains a site for inactivation.[11]
^Monzingo AF, Collins EJ, Ernst SR, Irvin JD, Robertus JD (October 1993). "The 2.5 A structure of pokeweed antiviral protein". Journal of Molecular Biology. 233 (4): 705–15.
doi:
10.1006/jmbi.1993.1547.
PMID8411176.
^Monzingo AF, Collins EJ, Ernst SR, Irvin JD, Robertus JD (October 1993). "The 2.5 A structure of pokeweed antiviral protein". Journal of Molecular Biology. 233 (4): 705–15.
doi:
10.1006/jmbi.1993.1547.
PMID8411176.