ADAMTS-4 Protein

ADAMTS4 Protein

title: ADAMTS-4 Protein

ADAMTS-4 (Aggrecanase-1)

<div class="infobox infobox-protein"> [@lemarchant2016]

| Property | Value | [@jansen2019]
|----------|-------| [@rodrigues2019]
| Protein Name | ADAMTS-4 | [@cross2006]
| Aliases | Aggrecanase-1, ADMP-1 | [@rolls2008]
| Gene | [ADAMTS4](/genes/adamts4) |
| UniProt ID | [O75173](https://www.uniprot.org/uniprot/O75173) |
| PDB IDs | [4WK7](https://www.rcsb.org/structure/4WK7), [3B2Z](https://www.rcsb.org/structure/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 |

</div>

Overview

ADAMTS-4 is a protein encoded by the [ADAMTS4](/genes/adamts4) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

Structure

ADAMTS-4 is a multidomain secreted zinc metalloproteinase with the following domain architecture (N→C):

...

ADAMTS4 Protein

title: ADAMTS-4 Protein

ADAMTS-4 (Aggrecanase-1)

<div class="infobox infobox-protein"> [@lemarchant2016]

| Property | Value | [@jansen2019]
|----------|-------| [@rodrigues2019]
| Protein Name | ADAMTS-4 | [@cross2006]
| Aliases | Aggrecanase-1, ADMP-1 | [@rolls2008]
| Gene | [ADAMTS4](/genes/adamts4) |
| UniProt ID | [O75173](https://www.uniprot.org/uniprot/O75173) |
| PDB IDs | [4WK7](https://www.rcsb.org/structure/4WK7), [3B2Z](https://www.rcsb.org/structure/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 |

</div>

Overview

ADAMTS-4 is a protein encoded by the [ADAMTS4](/genes/adamts4) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

Structure

ADAMTS-4 is a multidomain secreted zinc metalloproteinase with the following domain architecture (N→C):

Signal peptide (aa 1-29) — directs secretion

Propeptide (aa 30-212) — maintains latency; removed by [furin](/proteins/furin-protein) cleavage at the RRRR₂₁₂ site

Metalloproteinase (catalytic) domain (aa 213-434) — contains the zinc-binding HEXXHXXGXXH motif and the catalytic machinery; adopts a typical metzincin fold with a 5-stranded β-sheet, three α-helices, and a methionine-turn (Met-turn)

Disintegrin-like domain (aa 435-531) — structurally similar to snake venom disintegrins but lacks the RGD motif; contributes to substrate recognition

Thrombospondin type 1 (TSP-1) motif (aa 532-588) — mediates ECM binding and substrate interaction; contains a conserved CSVTCG sequence

Cysteine-rich domain (aa 589-696) — involved in substrate specificity and protein-protein interactions

Spacer domain (aa 697-837) — C-terminal domain that can be proteolytically removed; removal alters substrate specificity and activity

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.

Mechanism of Action

Activation

ADAMTS-4 is synthesized as a zymogen and activated through a multi-step process:

Proprotein cleavage — Furin or related proprotein convertases cleave the propeptide in the trans-Golgi network

Secretion — The activated enzyme is secreted into the extracellular space

C-terminal processing — MT4-MMP and other proteases can remove the spacer domain, generating truncated forms with altered substrate preferences

ECM anchoring — The TSP-1 motif and spacer domain mediate binding to ECM components, localizing enzymatic activity

Substrate Specificity

ADAMTS-4 cleaves multiple substrates relevant to neurodegeneration:

| Substrate | Cleavage Site | Relevance |
|-----------|---------------|-----------|
| [Aggrecan](/proteins/aggrecan) | E₃₇₃↓A₃₇₄ (IGD domain) | Cartilage degradation, CNS ECM |
| [Brevican](/proteins/brevican) | E₃₉₅↓S₃₉₆ | [Perineuronal net](/mechanisms/perineuronal-nets) degradation |
| [Versican](/proteins/versican) | E₄₄₁↓A₄₄₂ | ECM remodeling |
| [Neurocan](/proteins/neurocan) | Multiple sites | CNS proteoglycan turnover |
| [Amyloid-beta (Aβ)](/proteins/amyloid-beta) | Multiple sites | Aβ clearance in [AD](/diseases/alzheimers-disease) |
| Reelin | Not fully characterized | Synaptic signaling modulation |

Regulation

ADAMTS-4 activity is regulated at multiple levels:

• Transcriptional: [NF-κB](/entities/nf-kb), AP-1, and RUNX2 control gene expression in response to inflammatory signals
• Endogenous inhibitors: [TIMP-3](/proteins/timp3-protein) is the primary physiological inhibitor; binds the catalytic domain with nanomolar affinity
• Substrate availability: ECM composition and CSPG accessibility determine activity
• C-terminal processing: Removal of the spacer domain by MT4-MMP generates a more active truncated enzyme with broader substrate specificity

Role in Neurodegeneration

Alzheimer's Disease

ADAMTS-4 plays a dual role in [Alzheimer's disease](/diseases/alzheimers-disease) pathology:

Protective functions:

• Cleaves [Aβ peptides](/proteins/amyloid-beta) at multiple sites, promoting clearance and reducing amyloid plaque formation
• The protective ADAMTS4 I72V variant (in the propeptide domain) enhances enzymatic activity and Aβ degradation
• Upregulated in reactive [astrocytes](/cell-types/astrocytes) surrounding plaques, representing an endogenous defense mechanism

Pathological contributions:

• Excessive degradation of [brevican](/proteins/brevican) and other PNN components destabilizes synaptic connections
• PNN breakdown may facilitate [tau](/proteins/tau) pathology propagation between [neurons](/entities/neurons)
• Chronic neuroinflammation-driven ADAMTS-4 upregulation may exceed physiological ECM remodeling needs

Amyotrophic Lateral Sclerosis (ALS)

• ADAMTS-4 is upregulated in the spinal cord of ALS patients and [SOD1](/genes/sod1) mutant mice
• Contributes to neuromuscular junction destruction through ECM degradation
• Pharmacological inhibition or genetic deletion reduces motor neuron loss in SOD1-G93A mice

Spinal Cord Injury

• Therapeutic application of ADAMTS-4 degrades inhibitory CSPGs at the injury site
• Promotes axonal sprouting and functional recovery
• Recombinant ADAMTS-4 delivery is being explored as a regenerative strategy

Protein-Protein Interactions

Key interaction partners include:

• [TIMP-3](/proteins/timp3-protein) — endogenous metalloproteinase inhibitor
• Syndecan-1 — cell surface heparan sulfate proteoglycan; modulates activity
• [LRP1](/proteins/lrp1-protein) — mediates endocytic clearance of ADAMTS-4
• Fibronectin — ECM component; binds via TSP-1 motif
• [MT4-MMP (MMP-17)](/proteins/mmp17-protein) — processes the C-terminal spacer domain

Therapeutic Targeting

| 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 |

See Also

• [ADAMTS4 Gene](/genes/adamts4)
• [Perineuronal net](/mechanisms/perineuronal-nets)
• [AD](/diseases/alzheimers-disease)
• [Alzheimer's disease](/diseases/alzheimers-disease)

External Links

• [UniProt: O75173](https://www.uniprot.org/uniprot/O75173)
• [PDB structures](https://www.rcsb.org/search?q=uniprot:O75173)
• [GeneCards: ADAMTS4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADAMTS4)

References

[Tortorella et al., Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins (1999) (1999)](https://doi.org/10.1126/science.284.5420.1664)

[Mosyak et al., Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5 (2008) (2008)](https://doi.org/10.1002/pro.5560170416)

[Lemarchant et al., ADAMTS proteoglycanases in the physiological and pathological central nervous system (2013) (2013)](https://doi.org/10.1111/jnc.12136)

[Lemarchant et al., ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis (2016) (2016)](https://doi.org/10.1186/s13024-016-0078-3)

[Jansen et al., Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk (2019) (2019)](https://doi.org/10.1038/s41588-018-0311-9)

[Rodrigues et al., ADAMTS4 variant associated with Alzheimer's disease risk reduces amyloid-beta levels (2019) (2019)](https://doi.org/10.1016/j.jalz.2019.06.4950)

[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)](https://doi.org/10.1016/j.brainres.2006.05.065)

[Rolls et al., Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation (2008) (2008)](https://doi.org/10.1371/journal.pmed.0050171)