Dynamics and functional differences between dendroaspin and rhodostomin: Insights into protein scaffolds in integrin recognition

Cheng, Chi-Wen; Chen, Yi Chun; Shiu, Jia Hau; Chang, Yao; Chang, Yung Sheng; Huang, Chun Hau; Chen, Chiu Yueh; Chuang, Woei Jer

doi:10.1002/pro.2169

Cited by 6 publications

(7 citation statements)

References 49 publications

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“…The expression of Rho mutants, including 48 PRGDMP- 65 PR, 48 PRGDMP- 65 PRNGLYG, 48 PRGDMP- 65 PRNPWNG, 48 ARGDWN- 65 P, 48 ARGDWN- 65 PR, 48 ARGDWN- 65 PPRY, 48 ARGDWN- 65 PRYH, 48 ARGDWN- 65 PRNGLYG, and 48 ARGDWN- 65 PRNPWNG, in P . pastoris and purification were accomplished by following previously described protocols [ 26 – 28 ].…”

Section: Methodsmentioning

confidence: 99%

Effects of the RGD loop and C-terminus of rhodostomin on regulating integrin αIIbβ3 recognition

et al. 2017

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Rhodostomin (Rho) is a medium disintegrin containing a 48PRGDMP motif. We here showed that Rho proteins with P48A, M52W, and P53N mutations can selectively inhibit integrin αIIbβ3. To study the roles of the RGD loop and C-terminal region in disintegrins, we expressed Rho 48PRGDMP and 48ARGDWN mutants in Pichia pastoris containing 65P, 65PR, 65PRYH, 65PRNGLYG, and 65PRNPWNG C-terminal sequences. The effect of C-terminal region on their integrin binding affinities was αIIbβ3 > αvβ3 ≥ α5β1, and the 48ARGDWN-65PRNPWNG protein was the most selective integrin αIIbβ3 mutant. The 48ARGDWN-65PRYH, 48ARGDWN-65PRNGLYG, and 48ARGDWN-65PRNPWNG mutants had similar activities in inhibiting platelet aggregation and the binding of fibrinogen to platelet. In contrast, 48ARGDWN-65PRYH and 48ARGDWN-65PRNGLYG exhibited 2.9- and 3.0-fold decreases in inhibiting cell adhesion in comparison with that of 48ARGDWN-65PRNPWNG. Based on the results of cell adhesion, platelet aggregation and the binding of fibrinogen to platelet inhibited by ARGDWN mutants, integrin αIIbβ3 bound differently to immobilized and soluble fibrinogen. NMR structural analyses of 48ARGDWN-65PRYH, 48ARGDWN-65PRNGLYG, and 48ARGDWN-65PRNPWNG mutants demonstrated that their C-terminal regions interacted with the RGD loop. In particular, the W52 sidechain of 48ARGDWN interacted with H68 of 65PRYH, L69 of 65PRNGLYG, and N70 of 65PRNPWNG, respectively. The docking of the 48ARGDWN-65PRNPWNG mutant into integrin αIIbβ3 showed that the N70 residue formed hydrogen bonds with the αIIb D159 residue, and the W69 residue formed cation-π interaction with the β3 K125 residue. These results provide the first structural evidence that the interactions between the RGD loop and C-terminus of medium disintegrins depend on their amino acid sequences, resulting in their functional differences in the binding and selectivity of integrins.

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Section: Methodsmentioning

confidence: 99%

Effects of the RGD loop and C-terminus of rhodostomin on regulating integrin αIIbβ3 recognition

et al. 2017

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“…As previously mentioned in this work, disintegrins have a vast structural diversity. Within the disintegrin family there is a wide variety of disulfide bridge patterns and protein sizes and, at the same time, conserved structural features ( Huang T. F. et al, 1991 ; Coelho et al, 1999 ; Cidade et al, 2006 ; Cheng et al, 2012 ). For instance, jarastatin and triflavin disintegrins contain six disulfide bonds with the same cysteine pattern while the disintegrin domain of ADAM metalloproteinases present the same size, structural homology, and different disulfide pattern ( Huang T.-F. et al, 1991 ; Coelho et al, 1999 ; Cidade et al, 2006 ).…”

Section: Disintegrin Structure: Nmr and Crystallization Studiesmentioning

confidence: 99%

Structure-Function Relationship of the Disintegrin Family: Sequence Signature and Integrin Interaction

Vasconcelos

Estrada

David

et al. 2021

Front. Mol. Biosci.

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Disintegrins are small cysteine-rich proteins found in a variety of snake venom. These proteins selectively modulate integrin function, heterodimeric receptors involved in cell-cell and cell-matrix interaction that are widely studied as therapeutic targets. Snake venom disintegrins emerged from the snake venom metalloproteinase and are classified according to the sequence size and number of disulfide bonds. Evolutive structure and function diversification of disintegrin family involves a stepwise decrease in the polypeptide chain, loss of cysteine residues, and selectivity. Since the structure elucidation of echistatin, the description of the structural properties of disintegrins has allowed the investigation of the mechanisms involved in integrin-cell-extracellular matrix interaction. This review provides an analysis of the structures of all family groups enabling the description of an expanded classification of the disintegrin family in seven groups. Each group presents a particular disulfide pattern and sequence signatures, facilitating the identification of new disintegrins. The classification was based on the disintegrin-like domain of the human metalloproteinase (ADAM-10). We also present the sequence and structural signatures important for disintegrin-integrin interaction, unveiling the relationship between the structure and function of these proteins.

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“…This group is peculiar and probably has different activities, perhaps never identified in other 3FTxs around the world. Dendroaspin, the homologous protein of group 5, is a 3FTx containing a PRGDMP motif with potent activity on inhibiting integrins [ 60 ]. Sequences from group 5 do not have this motif and neither the RGD.…”

Section: Discussionmentioning

confidence: 99%

Three-Finger Toxins from Brazilian Coral Snakes: From Molecular Framework to Insights in Biological Function

Kleiz-Ferreira

Cirauqui

Trajano

et al. 2021

Toxins

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Studies on 3FTxs around the world are showing the amazing diversity in these proteins both in structure and function. In Brazil, we have not realized the broad variety of their amino acid sequences and probable diversified structures and targets. In this context, this work aims to conduct an in silico systematic study on available 3FTxs found in Micrurus species from Brazil. We elaborated a specific guideline for this toxin family. First, we grouped them according to their structural homologue predicted by HHPred server and further curated manually. For each group, we selected one sequence and constructed a representative structural model. By looking at conserved features and comparing with the information available in the literature for this toxin family, we managed to point to potential biological functions. In parallel, the phylogenetic relationship was estimated for our database by maximum likelihood analyses and a phylogenetic tree was constructed including the homologous 3FTx previously characterized. Our results highlighted an astonishing diversity inside this family of toxins, showing some groups with expected functional similarities to known 3FTxs, and pointing out others with potential novel roles and perhaps structures. Moreover, this classification guideline may be useful to aid future studies on these abundant toxins.

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Dynamics and functional differences between dendroaspin and rhodostomin: Insights into protein scaffolds in integrin recognition

Cited by 6 publications

References 49 publications

Effects of the RGD loop and C-terminus of rhodostomin on regulating integrin αIIbβ3 recognition

Effects of the RGD loop and C-terminus of rhodostomin on regulating integrin αIIbβ3 recognition

Structure-Function Relationship of the Disintegrin Family: Sequence Signature and Integrin Interaction

Three-Finger Toxins from Brazilian Coral Snakes: From Molecular Framework to Insights in Biological Function

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