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Semaphorin 3A—Glycosaminoglycans Interaction As Therapeutic Target for Axonal Regeneration

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Semaphorin 3A—Glycosaminoglycans Interaction As Therapeutic Target for Axonal Regeneration pharmaceuticals Article Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration Yolanda Pérez 1,* , Roman Bonet 2, Miriam Corredor 2, Cecilia Domingo 2, Alejandra Moure 2, Àngel Messeguer 2, Jordi Bujons 2 and Ignacio Alfonso 2,* 1 NMR Facility, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain 2 Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain; [email protected] (R.B.); [email protected] (M.C.); [email protected] (C.D.); [email protected] (A.M.); [email protected] (À.M.); [email protected] (J.B.) * Correspondence: [email protected] (Y.P.); [email protected] (I.A.) Abstract: Semaphorin 3A (Sema3A) is a cell-secreted protein that participates in the axonal guidance pathways. Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal growth and propagation. Therefore, interfering with Sema3A signaling is proposed as a therapeutic target for achieving functional recovery after CNS injuries. It has been shown that Sema3A adheres to the proteoglycan component of the extracellular matrix (ECM) and selectively binds to heparin and chondroitin sulfate-E (CS-E) glycosaminoglycans (GAGs). We hypothesize that Citation: Pérez, Y.; Bonet, R.; the biologically relevant interaction between Sema3A and GAGs takes place at Sema3A C-terminal Corredor, M.; Domingo, C.; polybasic region (SCT). The aims of this study were to characterize the interaction of the whole Moure, A.; Messeguer, À.; Bujons, J.; Sema3A C-terminal polybasic region (Sema3A 725–771) with GAGs and to investigate the disruption Alfonso, I. Semaphorin of this interaction by small molecules. Recombinant Sema3A basic domain was produced and we 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal used a combination of biophysical techniques (NMR, SPR, and heparin affinity chromatography) Regeneration. Pharmaceuticals 2021, to gain insight into the interaction of the Sema3A C-terminal domain with GAGs. The results 14, 906. https://doi.org/10.3390/ demonstrate that SCT is an intrinsically disordered region, which confirms that SCT binds to GAGs ph14090906 and helps to identify the specific residues involved in the interaction. NMR studies, supported by molecular dynamics simulations, show that a new peptoid molecule (CSIC02) may disrupt the Academic Editors: interaction between SCT and heparin. Our structural study paves the way toward the design of new Jesus Jimenez-Barbero and molecules targeting these protein–GAG interactions with potential therapeutic applications. Óscar Millet Keywords: semaphorin 3A; NMR; glycosaminoglycan–protein interaction; peptoids Received: 4 August 2021 Accepted: 1 September 2021 Published: 7 September 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in The extracellular matrix (ECM) is a dynamic three-dimensional network of macro- published maps and institutional affil- molecules that offers structural support for the cells and tissues and provides a microen- iations. vironment that regulates neural cell development and activity [1]. One of the building blocks of these networks are the proteoglycans (PGs). Proteoglycans are constituted by core proteins and one or several attached glycosaminoglycan (GAG) chains. PGs are present in ECM and on the cell membrane surface. GAGs play numerous biological roles mediated by the interaction with a variety of proteins [2–5]. GAG–protein interactions Copyright: © 2021 by the authors. participate in a variety of human diseases, including cardiovascular diseases, infections, Licensee MDPI, Basel, Switzerland. This article is an open access article neurodegenerative processes, and tumors [6,7]. Numerous experiments have established distributed under the terms and that the protein Semaphorin 3A (Sema3A) co-localizes with both cell surface and ECM conditions of the Creative Commons chondroitin/heparan sulfate proteoglycans (CSPGs/HSPGs) [8–10]. Sema3A interacts with Attribution (CC BY) license (https:// CSPGs in perineuronal nets (PNN, one form of ECM in the central nervous system (CNS)), creativecommons.org/licenses/by/ depending, among other features, on the sulfation pattern [10–13]. Early data showed 4.0/). that heparin enhances Sema3A binding to neuropilin-1-expressing cells and potentiates Pharmaceuticals 2021, 14, 906. https://doi.org/10.3390/ph14090906 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 24 Pharmaceuticals 2021, 14, 906 2 of 24 heparin enhances Sema3A binding to neuropilin-1-expressing cells and potentiates its growthits growth cone cone collapsing collapsing activity activity [8]. [Sema3A8]. Sema3A modulates modulates PNN PNN plasticity plasticity and and the the coexist- coexis- encetence of ofboth both Sema3A Sema3A and and chondroitin chondroitin sulfate sulfate (CS) (CS) on on the the neuronal neuronal surface surface gives gives stronger stronger plasticityplasticity restriction restriction in in PNN PNN [13] [13. ].These These studies studies support support the the contribution contribution of of CSPGs CSPGs to to the the Sema3ASema3A-Nrp-Plxn-Nrp-Plxn (Nr (Nrpp = =N Neuropilin;europilin; Plx Plxnn = =Plexin) Plexin) signaling signaling complex complex (Figure (Figure 1)1.). FigureFigure 1. 1.SchematicSchematic illustration illustration of of the the mechanism mechanism of of action action proposed proposed for for our our small small cationic cationic peptidomimetics peptidomimetics through through the the directdirect inhibition inhibition of of a abiologically biologically relevant relevant Sema3A Sema3A polybasic polybasic C C-terminal-terminal region region (SCT) (SCT)–GAG–GAG interaction. interaction. Sema3A Sema3A form formss ternaryternary complexes complexes with with its its receptor receptor proteins proteins (Nrps (Nrps-Plxs;-Plxs; Nrp1 Nrp1-PlxnA2-PlxnA2 is isas as example example of of interaction interaction partners). partners). The The figure figure shows the proposed inhibition mechanism of the Sema3A pathway by interfering the colocalization of secreted Sema3A shows the proposed inhibition mechanism of the Sema3A pathway by interfering the colocalization of secreted Sema3A with its receptor proteins (Nrp1-PlxnA2) due to CSIC02 binding to GAG sites. Long black lines represent the protein part with its receptor proteins (Nrp1-PlxnA2) due to CSIC02 binding to GAG sites. Long black lines represent the protein part of proteoglycans (PGs), red lines represent negatively charged sugar (GAG) chains. Sema3A/Nrp1/PllnxA2 domains: PSI (plexinof proteoglycans-semaphorin (PGs),-integrin), red Ig lines (immu representnoglobulin), negatively SCT (basic), charged IPT sugar (transcription (GAG) chains. factors), Sema3A/Nrp1/PllnxA2 GAP (GTPase-Activating domains: Pro- tein),PSI (plexin-semaphorin-integrin),a1/a2 (CUB), b1/b2 (FV/VIII), and Ig (immunoglobulin), c (MAM). SCT (basic), IPT (transcription factors), GAP (GTPase-Activating Protein), a1/a2 (CUB), b1/b2 (FV/VIII), and c (MAM). Sema3A is a member of the class-3 secreted Semaphorins. Semaphorins are classified on the Sema3Abasis of the isa specific member structure of the class-3 of their secreted C-terminal Semaphorins. domains [14] Semaphorins. Semaphorin are class classi--3 arefied secreted on the proteins basis of thecontaining specific a structure C-terminal of theirpolybasic C-terminal domain, domains an Ig-like [14 ].C2 Semaphorin-type (im- munoglobulinclass-3 are secreted-like) domain, proteins a containing PSI domain a, C-terminal and a Sema polybasic domain.domain, The Semaphorins an Ig-like C2-typerecep- (immunoglobulin-like) domain, a PSI domain, and a Sema domain. The Semaphorins re- tors, neuropilins and plexins, are expressed in a variety of cell types, including neurons, ceptors, neuropilins and plexins, are expressed in a variety of cell types, including neurons, endothelial cells, and cancer cells. Sema3A was initially characterized as an axon guidance endothelial cells, and cancer cells. Sema3A was initially characterized as an axon guidance molecule that takes part in regulating the process by which axon growth cones are di- molecule that takes part in regulating the process by which axon growth cones are directed rected to their appropriate targets during the nervous system growth. In the adult CNS, to their appropriate targets during the nervous system growth. In the adult CNS, Sema3A Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenera- acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal tive axonal growth and sprouting [12]. In addition, Sema3A can also function as chemo- growth and sprouting [12]. In addition, Sema3A can also function as chemo-attractive attractive agent, stimulating the growth of apical dendrites [15]. Moreover, class-3 Sema- agent, stimulating the growth of apical dendrites [15]. Moreover, class-3 Semaphorins phorins also play a role in many processes outside the nervous system, as tumor progres- also play a role in many processes outside the nervous system, as tumor progression or sion or suppression [16,17] or in the immune system [18,19] and are attracting much at- suppression [16,17] or in the immune system [18,19] and are attracting much attention as tention as potential therapeutic targets [20,21]. potential therapeutic targets [20,21]. PNNsPNNs are are
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