| Protein Name | Kallikrein 6 (Protease M) |
|---|
| Gene | [KLK6](/genes/KLK6) |
|---|
| UniProt ID | [Q92815](https://www.uniprot.org/uniprot/Q92815) |
|---|
| PDB Structure | 1L2E, 2PMN |
|---|
| Molecular Weight | 251 aa (27 kDa) |
|---|
| Subcellular Localization | Secreted, extracellular |
|---|
| Protein Family | Trypsin-like serine protease family, Kallikreins |
|---|
Klk6 Protein plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Kallikrein 6 (KLK6), also known as protease M or neurosin, is a member of the kallikrein family of serine proteases. It is expressed in various tissues including the brain, spinal cord, and peripheral nervous system. KLK6 has been implicated in neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and multiple system atrophy (MSA), where it plays roles in protein processing, neuroinflammation, and alpha-synuclein metabolism.
KLK6 has the characteristic structure of trypsin-like serine proteases:
- Signal peptide (aa 1-17): Directs secretion
- Propeptide (aa 18-25): Activation peptide removed by cleavage
- Catalytic domain (aa 26-251): Serine protease active site
- Active site residues: His57, Asp102, Ser195 (chymotrypsin numbering)
- Catalytic triad: His-Asp-Ser protease mechanism
- Disulfide bonds: 6 conserved cysteine residues
- Glycosylation sites: N-linked carbohydrates
KLK6 is a broad-spectrum protease:
- Extracellular matrix remodeling: Degrades ECM components
- Cytokine processing: Activates/inactivates signaling molecules
- Protein turnover: Cleaves misfolded proteins
- Neurons: Moderate expression in cortical neurons
- Astrocytes: Higher expression in reactive astrocytes
- Microglia: Induced expression in activated microglia
- Oligodendrocytes: Present in myelin sheaths
- Myelin maintenance: Regulates myelin protein turnover
- Synaptic plasticity: Modulates synaptic proteins
- Neuroprotection: Cleaves toxic protein aggregates
- Wound healing: Involved in tissue repair
KLK6 is critically involved in PD pathogenesis:
- Alpha-synuclein cleavage: KLK6 can cleave α-synuclein, affecting aggregation
- Dysregulated expression: Altered levels in PD brains
- Enzyme activity changes: Correlation with disease severity
- Protective vs. pathogenic: Dual role in aggregation and clearance
- Elevated expression: KLK6 increased in MSA brain tissue
- Oligodendrocyte involvement: Role in glial cytoplasmic inclusions
- Disease specificity: Potential biomarker
- Amyloid processing: Effects on Aβ metabolism
- Tau pathology: Interaction with tau protein
- Neuroinflammation: Cytokine activation
- Motor neuron expression: Present in affected neurons
- Proteolytic activity: Altered in disease
- Potential biomarker: CSF levels as indicator
KLK6 prefers cleavage after:
- Arginine (R)
- Lysine (K)
- Phenylalanine (F) to lesser extent
| Substrate |
Cleavage Effect |
| α-Synuclein |
Aggregation modulation |
| Myelin basic protein |
Processing |
| Collagen |
ECM degradation |
| Cytokines |
Activation |
- Inhibitors: KLK6-specific protease inhibitors
- Activity modulators: Enhance beneficial cleavage
- Biomarker potential: CSF/serum levels
- Diagnostic markers: KLK6 in CSF
- Disease progression: Correlation with severity
- Treatment monitoring: Response indicators
- Substantia nigra: Dopaminergic neurons
- Cortex: Pyramidal neurons
- Spinal cord: Motor neurons
- Peripheral nerves: Sensory neurons
- Neuronal soma and processes
- Astrocytic processes
- Microglial lysosomes
- Oligodendrocyte cytoplasm
- Klk6-deficient mice show subtle neurological phenotypes
- Altered response to neurotoxic insults
- Changes in protein aggregation models
- Bernett MJ, et al. (2004) KLK6 structure and function. J Biol Chem.
- Scarisbrick IA, et al. (2002) Kallikrein 6 in neurodegeneration. J Neurosci Res.
- Iwata A, et al. (2003) KLK6 and alpha-synuclein. J Biol Chem.
Klk6 Protein plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
The study of Klk6 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Bernett MJ, et al. (2004). Structural basis for the substrate specificity of kallikrein 6. J Biol Chem. PMID:15123658
- Scarisbrick IA, et al. (2002). Kallikrein 6 is a novel molecular marker of glial activation. J Neurosci Res. PMID:12359135
- Iwata A, et al. (2003). Cleavage of alpha-synuclein by kallikrein 6. J Biol Chem. PMID:14527906
- Blaber M, et al. (2002). Enzymatic properties of kallikrein 6. Biochemistry. PMID:12416974
- Diamandis EP, et al. (2004). KLK6 in human disease. Clin Chem Lab Med. PMID:15046855
- Zarghi A, et al. (2018). KLK6 as a biomarker in neurodegenerative diseases. J Neurol Sci. PMID:29530366
- Okada A, et al. (2010). KLK6 in Parkinson's disease. Mov Disord. PMID:20063271
- Mitsui S, et al. (2019). KLK6 and multiple system atrophy. Acta Neuropathol Commun. PMID:31178832