Cathepsin D is a
protein that in humans is encoded by the ''CTSD''
gene.
This gene encodes a
lysosomal aspartyl protease composed of a
protein dimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...
of
disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in
lysosomes.
The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments.
This
proteinase, which is a member of the peptidase A1 family, has a specificity similar to but narrower than that of
pepsin A. Transcription of the ''CTSD'' gene is initiated from several sites, including one that is a start site for an
estrogen-regulated transcript.
Mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
in this gene are involved in the pathogenesis of several diseases, including
breast cancer and possibly
Alzheimer disease.
Homozygous deletion of the ''CTSD'' gene leads to early lethality in the postnatal phase.
Deficiency of ''CTSD'' gene has been reported an underlying cause of
neuronal ceroid lipofuscinosis (NCL).
Structure
Gene
The ''CTSD'' gene is located at
chromosome 11.
Protein
The catalytic sites of cathepsin D include two critical aspartic residues (
amino acid 33 and 231) located on the 14 kDa and 34kDa chains.
The ultimate form of mature cathepsin D is composed of 337 amino acid residues, 196 amino acid residues in the heavy chain and 141 in the light chain. These two chains are linked by the
hydrophobic effect.
Function
The optimum pH for cathepsin D in vitro is 4.5-5.0.
Cathepsin-D is an aspartic protease that depends critically on protonation of its active site Asp residue. Along with Asp-protonation, lower pH also leads to conformational switch in cathepsin-D : the
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
segment of the protease moves out of the active site as pH drops.
Similar to other aspartic protainases, cathepsin D accommodates up to 8 amino acid residues in the binding cleft of the active site. The main physiological functions of cathepsin D consist of metabolic degradation of intracellular proteins, activation and degradation of
polypeptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A p ...
hormones
A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and beh ...
and
growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and regulation of
programmed cell death.
Cathepsin D can also be found in the extracellular space
and it is one of the few cathepsins, that shows some activity at neutral pH. It is able to activate the growth factors
VEGF-C and
VEGF-D, which might partly explain its relevance for tumor progression.
Clinical significance
The NCLs present with progressive loss of visual function and neurodevelopmental decline,
seizure,
myoclonic jerks
Myoclonus is a brief, involuntary, irregular (lacking rhythm) twitching of a muscle or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus (myo "muscle", clonic "jerk") describes a medical sign and, generally, i ...
and premature death. The ''CTSD'' gene is one of the identified eight genes the deficiency of which is responsible for NCLs.
It has been reported that a homozygous single nucleotide duplication in exon 6 could alter the
reading frame and causes a premature stop codon at position 255. Over-expression of cathepsin D stimulates tumorigenicity and
metastasis as well as initiation of tumor apoptosis. This protease has been regarded an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis.
Knock-out of ''CTSD'' gene would cause intestinal
necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
and
hemorrhage and increase apoptosis in
thymus, indicating that cathepsin D is required in certain epithelial cells for tissue remodeling and renewal.
It is also reported that there might be a strong effect for CTSD genotype on Alzheimer disease risk in male.
Cathepsin D enzymatic activity induces hydrolytic modification of apolipoprotein B-100-containing lipoproteins, including LDL, which means it may be involved in atherosclerosis as well.
Interaction
*
Pepstatin
*
Transglutaminase 2
*
HEBP1
Heme binding protein 1 is a protein that in humans is encoded by the HEBP1 gene.
Function
The full-length protein encoded by this gene is an intracellular tetrapyrrole-binding protein. This protein includes a natural chemoattractant peptide of 2 ...
*
A2M
*
Ceramide
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
* The
MEROPS online database for peptidases and their inhibitors
A01.009 GeneReviews/NIH/NCBI/UW entry on Neuronal Ceroid-LipofuscinosesPDBe-KBprovides an overview of all the structure information available in the PDB for Human Cathepsin D
{{Portal bar, Biology, border=no
Proteases
EC 3.4.23
Cathepsins