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Introduction

Cathepsin B is one of approximately a dozen members of the Cathepsin(Greek kata- "down" and hepsein "boil”) family, a group of proteases widely distributed in animal cells with vital roles in a variety of processes, including intracellular protein turnover, immune response triggered apoptosis, and extracellular bone resorption. Because most of these enzymes are activated in low pH environments, their functions are generally localized to the interior of lysosomes. One notable exception to this rule is Cathepsin K, which is secreted extracellularly by osteoclasts during bone resorption. They share the general function of degrading polypeptides, and are differentiated by their respective structures, catalytic mechanisms, and substrate specificities ^{[1] [2]}. Cathepsin B is coded for by the gene CTSB (homo sapiens) located on chromosome 8 ^[3], and is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and several other organisms ^[4]. Its general function in normal cells is autophagy; the lysosome-mediate catabolism and recycling of dysfunctional cytoplasmic proteins and damaged organelles. Aside from helping to maintain normal cellular metabolism, it plays a major role in apoptosis of stressed cells, as in starvation ^[5]. It has also been implicated in lipopolysaccharide induced apoptosis ^[6], as well as TNF-α mediated apoptosis in hepatocytes ^[7]. Cathepsin B is normally synthesized as an inactive zymogen, and is processed by other proteases in the low pH environment of the lysosome. In certain cases however, activation can be achieved in neutral pH when bound to certain negatively charged molecules, like heparin ^[8]. One important implication of this is that Cathepsin B is capable of extracellular peptidase activity targeting extracellular matrix proteins ^{[9] [10]}. Observation of this type of activity, as well as evidence of over-expression in cancer cells has made Cathepsin B a suspect in studies of factors affecting tumor invasion and cancer metastasis ^{[11] [12] [13]}.

Structure

It is originally translated as a 37,822 Da, 339 residue zymogen, and is 254 residues long in its processed form ^[14]. During processing, peptides 1-79 are removed, as well as the last 5, 334-339. Two residues, 127 and 128 are removed from the middle, yielding two-chain molecule composed of a 47 residue (Leu1-Asn47) and a 205 residue (Val50-Asp254) cross-linked with six and sharing a ligand (EP0). Cathepsin B is usually found as a dimer of two of these two-chain molecules ^[15].

Mechanism

Cathepsin is a member of the peptidase C1 family ^[16], a grouping of cysteine proteases (or thiol proteases) containing a characteristic Cys-His catalytic dyad. It is an endopeptidase, but also displays peptidyl-dipeptidase activity by cleaving dipeptides at the C-terminus. It’s specificity for peptide bond hydrolysis is relatively broad, but some preference has been observed for Arg-Arg-/-Xaa sequences in small molecules ^[17]. The is composed of Cys29, His199 and Asn219 residues.

Medical Implications

Cancer

Due to the nature of it’s proteolytic activity and overexpression in many types of cancer cells, Cathepsin B has been indicated as playing an important role in the invasiveness of tumor cells, as well as the progression to malignancy ^{[18] [19]}.

HIV

There is some evidence that Cathepsin B plays a role in the CD4-independent infection of Human Immunodeficiency Virus ^[20].

Alzheimer’s disease

Cathepsin B was once thought to be involved in the conversions of β-amyloid precursor protein (APP) into the causative amyloid plaques definitive of Alzheimer’s, but this process is now know to be executed by β-secretase 1 (BACE1). Cathepsin B is now thought to digest APP into harmless products, and therefore to play a part in the body’s natural defense against Alzheimer’s ^[21].

Ebola

Some evidence exists of Cathepsin B playing a role in Ebola virus disease ^[22].

References