| Property | Value | [1]
|----------|-------| [2]
| Protein Name | ADAMTS-4 | [3]
| Aliases | Aggrecanase-1, ADMP-1 | [4]
| Gene | ADAMTS4 |
| UniProt ID | O75173 |
| PDB IDs | 4WK7, 3B2Z |
| Molecular Weight | ~91 kDa (mature form) |
| Protein Family | ADAMTS metalloproteinase family |
| Enzyme Classification | EC 3.4.24.82 |
| Subcellular Localization | Secreted, extracellular space |
| Post-translational Modifications | Furin cleavage, glycosylation, C-terminal processing |
ADAMTS-4 is a protein encoded by the ADAMTS4 gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
ADAMTS-4 is a multidomain secreted zinc metalloproteinase with the following domain architecture (N→C):
The catalytic domain coordinates a zinc ion through three histidine residues (H369, H373, H379) and a glutamate (E370) acts as the general base for catalysis.
ADAMTS-4 is synthesized as a zymogen and activated through a multi-step process:
ADAMTS-4 cleaves multiple substrates relevant to neurodegeneration:
| Substrate | Cleavage Site | Relevance |
|---|---|---|
| Aggrecan | E₃₇₃↓A₃₇₄ (IGD domain) | Cartilage degradation, CNS ECM |
| Brevican | E₃₉₅↓S₃₉₆ | Perineuronal net degradation |
| Versican | E₄₄₁↓A₄₄₂ | ECM remodeling |
| Neurocan | Multiple sites | CNS proteoglycan turnover |
| Amyloid-beta (Aβ) | Multiple sites | Aβ clearance in AD |
| Reelin | Not fully characterized | Synaptic signaling modulation |
ADAMTS-4 activity is regulated at multiple levels:
ADAMTS-4 plays a dual role in Alzheimer's disease pathology:
Protective functions:
Pathological contributions:
Key interaction partners include:
| Approach | Status | Notes |
|---|---|---|
| ADAMTS-4 activity enhancers | Preclinical | For AD Aβ clearance |
| Selective ADAMTS-4 inhibitors | Phase I (osteoarthritis) | Risk of CNS side effects |
| Recombinant ADAMTS-4 delivery | Preclinical | Spinal cord injury repair |
| Gene therapy (ADAMTS4 overexpression) | Preclinical | AAV-mediated delivery to CNS |
Jansen et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk (2019). 2019. ↩︎
Rodrigues et al. ADAMTS4 variant associated with Alzheimer's disease risk reduces amyloid-beta levels (2019). 2019. ↩︎
Cross et al. ADAMTS-1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes (2006). 2006. ↩︎
Rolls et al. Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation (2008). 2008. ↩︎