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Cathepsin B

Cathepsin B is a very complex protein which is a part of the super family of papain-like cystein proteases. These papain-like cysteine proteases are abundant in nature and can be found in baculovirus, eubacteria, yeast, plants, and animals. They are synthesized as inactive proenzymeswith N-terminal pro-peptide regions. The pro-peptide plays an important role as an inhibitor of enzymatic activity. A number of cysteine proteases are located within lysosomes and they have very specific functions in endo and exopeptidase activity. Cathepsin B is synthesized as a pre-proenzyme of 339 amino acid residues and it can act as an endopeptidase. Its activity is inhibited by a2-macroglobulin . The most crucial functions of Cathepsin B are that it is implicated in the turnover of proteins and carries out different roles in maintaining the normal metabolism of cells. Cathepsin B is found in humans and other mammals and it is encoded by a single gene and this gene exhibits a high degree of sequence homology to other cysteine proteases of the papain super family. However, in parasitic helmiths and free-living nematodes, the Cathepsin B genes can be seen as large multigene families instead of just one single gene shown in humans and mammals. The function of this Cathepsin B gene has not been verified for sure, but research is showing that Cathepsin B could be involved in induction of protective immunity. In diseases, such as cancer and arthritis, Cathepsin B gene shows up regulation and in Alzheimer’s disease down regulation is shown.

Structure

Isolated from human liver, the protein Cathepsin B has a very unique structure. Human Cathepsin B contains 14 cysteine residues, with Cys29 representing the active site cysteine, and 12 other cysteine residues found to be involved in disulphide bridges. Also, Cathepsin B contains six dilsulfide bridges which are enclosed to the amino-terminal half of the molecule. Two of the cysteine residues (Cys 29 and Cys 240) are unpaired. The crystal structure of Cathepsin B consist of a double-chain form, with one light chain and one heavy chain composed of residues Leu1-Asn47 and Val50-Asp254. Some other features of Cathepsin B is that it has a diameter of 50 angstroms and a thickness of 30 angstroms. Also, you can see that there is a marked incision on the structure which represents the active site cleft. The polypeptide chain is described as being folded into two distinct domains which are known to interact with one another through an extended polar interface which opens to the V-shaped active site cleft. The left-hand” L” domain is formed by the amino-terminal half of the polypeptide chain up to about Tyr 148 and by the last carboxy-terminal residues. The right hand “R” domain is composed of the first ten residues and the carboxy-terminal half of the polypeptide chain. The amino and the carboxy-terminal ends act as ‘straps’ which help in clamping both domains together.

Function

The protein Cathepsin B has many molecular functions. Some of these functions include endopeptidase activity, cysteine-type endopeptidase activity, protein binding, peptidase activity, cysteine-type peptidase activity, hydrolase activity, kininogen binding, and peptide binding.

Mechanism of Action

Medical Implications or Possible Application

References