NMR Characterization of the Interactions Between Glycosaminoglycans and Proteins

Bu, Changkai; Jin, Lan

doi:10.3389/fmolb.2021.646808

Cited by 16 publications

(13 citation statements)

References 169 publications

(160 reference statements)

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“…Moreover, the other SCT variants analyzed (the mutant SCT RR/QH and the constructs corresponding to the processing of Furin sites 3 and 4 (SCT FS3 and SCT FS4 ) show similar affinities for heparin, suggesting low influence of the removed or mutated amino acids. It is evident from these results that the measured affinities are in agreement with the values in the literature for GAG binding proteins [ 55 , 56 ]. On the other hand, when heparin is added into the SCT WT solution, the CD spectrum ( Figure 3 b) shows a shifting of the minimum and the curve flattening, suggesting some slight conformational change upon heparin binding.…”

Section: Resultssupporting

confidence: 89%

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

et al. 2021

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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 the biologically relevant interaction between Sema3A and GAGs takes place at Sema3A C-terminal polybasic region (SCT). The aims of this study were to characterize the interaction of the whole Sema3A C-terminal polybasic region (Sema3A 725–771) with GAGs and to investigate the disruption of this interaction by small molecules. Recombinant Sema3A basic domain was produced and we used a combination of biophysical techniques (NMR, SPR, and heparin affinity chromatography) to gain insight into the interaction of the Sema3A C-terminal domain with GAGs. The results demonstrate that SCT is an intrinsically disordered region, which confirms that SCT binds to GAGs 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 interaction between SCT and heparin. Our structural study paves the way toward the design of new molecules targeting these protein–GAG interactions with potential therapeutic applications.

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Section: Resultssupporting

confidence: 89%

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

et al. 2021

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“…Nuclear magnetic resonance is widely used to study the conformation of GAGs alone or in complexes with proteins . In NMR, the behavior of two interacting molecules depends on the relative lifetimes of the species in the equilibrium and the strength of the magnetic field.…”

Section: Protein-glycosaminoglycan Interactionsmentioning

confidence: 99%

Glycosaminoglycans: What Remains To Be Deciphered?

Pérez

Makshakova

Angulo

et al. 2023

JACS Au

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Glycosaminoglycans (GAGs) are complex polysaccharides exhibiting a vast structural diversity and fulfilling various functions mediated by thousands of interactions in the extracellular matrix, at the cell surface, and within the cells where they have been detected in the nucleus. It is known that the chemical groups attached to GAGs and GAG conformations comprise “glycocodes” that are not yet fully deciphered. The molecular context also matters for GAG structures and functions, and the influence of the structure and functions of the proteoglycan core proteins on sulfated GAGs and vice versa warrants further investigation. The lack of dedicated bioinformatic tools for mining GAG data sets contributes to a partial characterization of the structural and functional landscape and interactions of GAGs. These pending issues will benefit from the development of new approaches reviewed here, namely (i) the synthesis of GAG oligosaccharides to build large and diverse GAG libraries, (ii) GAG analysis and sequencing by mass spectrometry (e.g., ion mobility-mass spectrometry), gas-phase infrared spectroscopy, recognition tunnelling nanopores, and molecular modeling to identify bioactive GAG sequences, biophysical methods to investigate binding interfaces, and to expand our knowledge and understanding of glycocodes governing GAG molecular recognition, and (iii) artificial intelligence for in-depth investigation of GAGomic data sets and their integration with proteomics.

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“…Glycosaminoglycans (GAGs) are heterogeneous long linear periodic anionic polysaccharides that consist of repeating disaccharide units 1 . The components of these disaccharide units may exhibit different sulfation patterns, which alter their conformational properties and binding characteristics 2,3 .…”

Section: Introductionmentioning

confidence: 99%

Explicit solvent repulsive scaling replica exchange molecular dynamics (RS‐REMD) in molecular modeling of protein‐glycosaminoglycan complexes

et al. 2022

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Glycosaminoglcyans (GAGs), linear anionic periodic polysaccharides, are crucial for many biologically relevant functions in the extracellular matrix. By interacting with proteins GAGs mediate processes such as cancer development, cell proliferation and the onset of neurodegenerative diseases. Despite this eminent importance of GAGs, they still represent a limited focus for the computational community in comparison to other classes of biomolecules. Therefore, there is a lack of modeling tools designed specifically for docking GAGs. One has to rely on existing docking software developed mostly for small drug molecules substantially differing from GAGs in their basic physico-chemical properties. In this study, we present an updated protocol for docking GAGs based on the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) that includes explicit solvent description. The use of this water model improved docking performance both in terms of its accuracy and speed. This method represents a significant computational progress in GAG-related research.

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NMR Characterization of the Interactions Between Glycosaminoglycans and Proteins

Cited by 16 publications

References 169 publications

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

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

Glycosaminoglycans: What Remains To Be Deciphered?

Explicit solvent repulsive scaling replica exchange molecular dynamics (RS‐REMD) in molecular modeling of protein‐glycosaminoglycan complexes

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