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):
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:
[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)