9DFF

G1 domain of human aggrecan bound to hyaluronan

Summary for 9DFF

• Entry DOI: 10.2210/pdb9dff/pdb
• Descriptor: Aggrecan core protein, 4-deoxy-alpha-L-threo-hex-4-enopyranuronic acid-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-beta-D-glucopyranuronic acid-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-beta-D-glucopyranuronic acid-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-beta-D-glucopyranuronic acid-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-beta-D-glucopyranuronic acid-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: extracellular matrix, hyaluronan, chondroitin sulfate proteoglycan, sugar binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 79441.41

Authors

Bouyain, S. (deposition date: 2024-08-29, release date: 2025-04-30, Last modification date: 2025-05-07)

Primary citation

Otsuka, M.Y.,Essel, L.B.,Sinha, A.,Nickerson, G.,Mejia, S.M.,Edge, A.,Matthews, R.T.,Bouyain, S.
Aggrecan immobilizes to perineuronal nets through hyaluronan-dependent and independent binding activities.
J.Biol.Chem., :108525-108525, 2025

PubMed Abstract: Aggrecan (ACAN) is a large, secreted chondroitin sulfate proteoglycan that includes three globular regions named G1, G2, G3, and is decorated with multiple glycosaminoglycan attachments between its G2 and G3 domains. The N-terminal G1 region interacts with the glycosaminoglycan hyaluronan (HA), which is an essential component of the vertebrate extracellular matrix. In the central nervous system, ACAN is found in perineuronal nets (PNNs), honeycomb-like structures that localize to the surface of parvalbumin-positive neurons in specific neural circuits. PNNs regulate the plasticity of the central nervous system, and it is believed that association between ACAN and HA is a foundational event in the assembly of these reticular structures. Here, we report the co-crystal structure of the G1 region of ACAN in the absence and presence of a HA decasaccharide and analyze the importance of the HA-binding activity of ACAN for its integration into PNNs. We demonstrate that the single immunoglobulin domain and the two Link modules that comprise the G1 region form a single structural unit, and that HA is clamped inside a groove that spans the length of the tandem Link domains. Introducing point mutations in the glycosaminoglycan-binding site eliminates HA-binding activity in ACAN, but, surprisingly, only decreases the integration of ACAN into PNNs. Thus, these results suggest that ACAN can be recruited into PNNs independently of its HA-binding activity.

PubMed: 40273987
DOI: 10.1016/j.jbc.2025.108525

Experimental method

X-RAY DIFFRACTION (2.59 Å)