Chondroitin sulfate proteoglycans: structure-function relationship with implication in neural development and brain disorders

Abstract

Chondroitin sulfate proteoglycans (CSPGS) are extracellular matrix components that contain two structural parts with distinct functions: a protein core and glycosaminoglycan (GAG) side chains. CSPGs are known to be involved in important cell processes like cell adhesion and growth, receptor binding, or cell migration. It is recognized that the presence of CSPGs is critical in neuronal growth mechanisms including axon guidance following injury of nervous system components such as spinal cord and brain. CSPGs are upregulated in the central nervous system after injury and participate in the inhibition of axon regeneration mainly through their GAG side chains. Recently, it was shown that some CSPGs members like aggrecan, versican, and neurocan were strongly involved in brain disorders like bipolar disorder (BD), schizophrenia, and ADHD. In this paper, we present the chemical structure-biological functions relationship of CSPGs, both in health state and in genetic disorders, addressing methods represented by genome-wide and crystallographic data as well as molecular modeling and quantitative structure-activity relationship.

Figure 1

Domain structure of human VCAN, ACAN, NCAN, and BCAN. The schematic representation was performed based on information retrieved from UniProt database [34], entries P13611 (human VCAN sequence), P16112 (human ACAN sequence), O14594 (human NCAN sequence), and Q96GW7 (human BCAN sequence). The four CSPGs present the following: (i) an N-terminal G1 domain comprising an immunoglobulin-like domain (Ig domain) and proteoglycan tandem repeats (PTR) domains involved in binding hyaluronic acid, (ii) a chondroitin sulfate attachment region, (iii) a C-terminal G3 domain comprising epidermal growth factor- (EGF-) like domains, a lectin-like domain, and a complement regulatory protein- (CRP-) like domain. The G2 domain, specific only for ACAN structure, comprises two PTR domains.

Figure 2

The crystal structures of the following NCAM fragments: (a) the first three N-terminal Ig modules (Ig1, Ig2, and Ig3), according to the crystal structure 1QZ1 [49]; (b) the third and fourth Ig modules (Ig3 and Ig4), according to the crystal structure 2XY1 [50]; and (c) first two fibronectin type III modules (FnIII,1 and FnIII,2), according to the crystal structure 2VKW [51]. The domains are labeled in the figure and are represented using different colors. Figures were made by Mernea M. using the free license software Pymol [52].

Figure 3

(a) Representation of the favorable (white polygons) and unfavorable (grey polygons) hydrophobic areas of risperidone (biological activity on D2 = 8.18) when its antagonist potency at dopamine D2 receptor is considered and (b) representation of the favorable (white polyhedral) and unfavorable (grey polyhedral) hydrophobic areas of risperidone (biological activity on 5HT2A = 9.76) when its antagonist potency at the serotonin 5HT2A receptor is considered [after Avram et al. [77], copyright permission].

Figure 4

(a) The structure of ACAN core protein in complex with tenascin-R FnIII repeats 3–5, as revealed by the crystal structure 1TDQ [78]. The tenascin-R fragment is represented as a light blue transparent surface that covers its backbone represented with the same color. ACAN core protein is represented with magenta and the three Ca²⁺ ions coordinated by ACAN are represented with yellow. (b) Detail on ACAN core protein (represented with magenta). The Ca²⁺ ions are represented with yellow and the residues involved in coordinating them are represented with green. Figures were made by Mernea M. using the free license software Pymol [52].