Cathepsin D is a fundamental enzyme present throughout the human body, playing a part in various cellular processes. It helps maintain the internal balance of cells by participating in the breakdown and recycling of cellular components. Understanding this enzyme provides insight into how our cells function and adapt.
What Cathepsin D Is
Cathepsin D is a lysosomal aspartyl protease, an enzyme that breaks down proteins. It is encoded by the CTSD gene in humans and is found within lysosomes, which are cellular compartments responsible for waste digestion and recycling. Its primary role involves breaking down proteins and activating inactive forms of other biologically active proteins within these compartments. Cathepsin D is a member of the peptidase A1 family, sharing some similarities with pepsin A, though its specificity for targets is more limited.
How Cathepsin D Works
Cathepsin D operates as a protein dimer, composed of two protein units. These units, a heavy chain and a light chain, are linked by disulfide bonds, both originating from a single precursor protein. Its catalytic activity enables it to break down other molecules, relying on two specific aspartic acid residues located at amino acid positions 97 and 295 within its structure. The mature form of cathepsin D consists of 337 amino acid residues, with 196 in the heavy chain and 141 in the light chain, held together by non-covalent interactions.
The enzyme functions optimally in acidic environments, with a pH between 4.5 and 5.0, a condition characteristic of lysosomes. This acidic pH causes a conformational change in cathepsin D, allowing its N-terminal segment to move away from the active site, enabling its function. Cathepsin D processes proteins, activates and breaks down hormones and growth factors, and processes enzyme precursors, activators, and inhibitors. It also plays a part in processing brain antigens and regulating programmed cell death. While mainly active in acidic conditions, cathepsin D can also exhibit some activity at a neutral pH, and it can be found outside the cell.
Cathepsin D and Human Health
Cathepsin D is involved in several human diseases. In breast cancer, elevated levels are observed and can stimulate tumor growth and spread. This enzyme’s presence has been linked to a less favorable outlook for patients, making it a recognized prognostic factor in various cancers.
The enzyme also plays a role in neurodegenerative conditions, such as Alzheimer’s disease. It processes proteins like amyloid precursor protein (APP) and tau, implicated in the progression of Alzheimer’s when not properly degraded. Mutations in the CTSD gene have been linked to neuronal ceroid lipofuscinosis (NCL), a severe neurodegenerative disorder. A complete absence of cathepsin D activity in NCL can lead to early death in newborns.
Cathepsin D is also implicated in atherosclerosis, a condition where plaque builds up inside arteries. Its enzymatic activity can modify lipoproteins such as LDL, connecting it to the development of this cardiovascular disease. Maintaining proper cathepsin D activity is important for cellular and overall human health, as dysregulation contributes to various pathological states.
The Different Forms of Cathepsin D
Cathepsin D exists in several forms within a cell. It is initially synthesized as an inactive precursor called pre-procathepsin D. This pre-proenzyme undergoes processing, including the removal of a signal peptide, to become procathepsin D, a 52 kDa glycoprotein.
Procathepsin D is then transported to lysosomes and endosomes, where it is further cleaved to form an intermediate, enzymatically active single-chain form, which is around 48 kDa. Subsequent processing by other enzymes, such as cysteine cathepsins B and L, results in the mature, active double-chain cathepsin D, composed of a heavy chain (about 34 kDa) and a light chain (around 14 kDa). These multiple forms can exhibit different activities and cellular locations.