Decoding Protein-protein Interactions: An Overview

Slater, Olivia; Miller, Bethany; Kontoyianni, Maria

doi:10.2174/1568026620666200226105312

Cited by 17 publications

(10 citation statements)

References 287 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Protein–protein interactions (PPIs) are universal and fundamental for cell activities. They employ many protein domains as the modules to mediate and construct the PPI network [ 1 , 2 ]. Src homology 3 (SH3) domain is one of the earliest discovered and widely studied PPI modules, which can recognize a diverse array of the proline-rich motifs (PRMs) [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode

Jia

Lin

et al. 2023

IJMS

View full text Add to dashboard Cite

SH3 domains are common protein binding modules. The target sequence of SH3 domains is usually a proline-rich motif (PRM) containing a minimal “PxxP” sequence. The mechanism of how different SH3 domains specifically choose their targets from vast PxxP-containing sequences is still not very clear, as many reported SH3/PRM interactions are weak and promiscuous. Here, we identified the binding of the SH3 domain of ASAP1 to the PRM of MICAL1 with a sub-μM binding affinity, and determined the crystal structure of ASAP1-SH3 and MICAL1-PRM complex. Our structural and biochemical analyses revealed that the target-binding pocket of ASAP1-SH3 contains two negatively charged patches to recognize the “xPx + Px+” sequence in MICAL1-PRM and consequently strengthen the interaction, differing from the typical SH3/PRM interaction. This unique PRM-binding pocket is also found in the SH3 domains of GTPase Regulator associated with focal adhesion kinase (GRAF) and Src kinase associated phosphoprotein 1 (SKAP1), which we named SH3AGS. In addition, we searched the Swiss-Prot database and found ~130 proteins with the SH3AGS-binding PRM in silico. Finally, gene ontology analysis suggests that the strong interaction between the SH3AGS-containing proteins and their targets may play roles in actin cytoskeleton regulation and vesicle trafficking.

show abstract

Section: Introductionmentioning

confidence: 99%

Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode

Jia

Lin

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Surface plasmon resonance demonstrated the NAM/F508del-CFTR interaction without providing the location of the binding site. Relevantly, molecular docking is instrumental in the prediction of binding site(s) [ 58 ], prompting us to use it for our aims. Due to the instability of NAM alone inside the DP1 sub-region, we computationally evaluated the binding of NAM outside the DP1.…”

Section: Resultsmentioning

confidence: 99%

Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing

Fossa

Uggeri

Orro

et al. 2022

IJMS

View full text Add to dashboard Cite

Cystic fibrosis is a hereditary disease mainly caused by the deletion of the Phe 508 (F508del) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. Cystic fibrosis remains a potentially fatal disease, but it has become treatable as a chronic condition due to some CFTR-rescuing drugs that, when used in combination, increase in their therapeutic effect due to a synergic action. Also, dietary supplementation of natural compounds in combination with approved drugs could represent a promising strategy to further alleviate cystic fibrosis symptoms. On these bases, we screened by in silico drug repositioning 846 small synthetic or natural compounds from the AIFA database to evaluate their capacity to interact with the highly druggable lumacaftor binding site of F508del-CFTR. Among the identified hits, nicotinamide (NAM) was predicted to accommodate into the lumacaftor binding region of F508del-CFTR without competing against the drug but rather stabilizing its binding. The effective capacity of NAM to bind F508del-CFTR in a lumacaftor-uncompetitive manner was then validated experimentally by surface plasmon resonance analysis. Finally, the capacity of NAM to synergize with lumacaftor increasing its CFTR-rescuing activity was demonstrated in cell-based assays. This study suggests the possible identification of natural small molecules devoid of side effects and endowed with the capacity to synergize with drugs currently employed for the treatment of cystic fibrosis, which hopefully will increase the therapeutic efficacy with lower doses.

show abstract

“…PPI networks provide insights into the co‐expression, fusion, neighbourhood and co‐localization of interactions between putative targets 25 . The names of the putative target genes were entered into the STRING database 26 (https://string-db.org/cgi/input.pl), the species was selected as ‘Homo sapiens’, and the confidence threshold was set to 0.4 to obtain the PPI network relationships of the putative targets.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of ligusticum cycloprolactam against neuroinflammation based on network pharmacology and experimental verification

Gao

Chen

et al. 2023

Clin Exp Pharma Physio

View full text Add to dashboard Cite

Ligustilide, a natural phthalide mainly derived from chuanxiong rhizomes and Angelica Sinensis roots, possesses anti-inflammatory activity, particularly in the context of the nervous system. However, its application is limited because of its unstable chemical properties. To overcome this limitation, ligusticum cycloprolactam (LIGc) was synthesized through structural modification of ligustilide. In this study, we combined network pharmacological methods with experimental verification to investigate the anti-neuroinflammatory effects and mechanisms of ligustilide and LIGc. Based on our network pharmacology analysis, we identified four key targets of ligustilide involved in exerting an anti-inflammatory effect, with the nuclear factor (NF)-κB signal pathway suggested as the main signalling pathway. To verify these results, we examined the expression of inflammatory cytokines and inflammation-related proteins, analysed the phosphorylation level of NF-κB, inhibitor of κBα (IκBα) and inhibitor of κB kinase α and β (IKKα+β), and evaluated the effect of BV2 cell-conditioned medium on HT22 cells in vitro. Our results, demonstrate for the first time that LIGc can downregulate the activation of the NF-κB signal pathway in BV2 cells induced by lipopolysaccharide, suppress the production of inflammatory cytokines and reduce nerve injury in HT22 cells mediated by BV2 cells. These findings suggest that LIGc inhibits the neuroinflammatory response mediated by BV2 cells, providing strong scientific support for the development of anti-inflammatory drugs based on natural ligustilide or its derivatives. However, there are some limitations to our current study. In the future, further experiments using in vivo models may provide additional evidence to support our findings.

show abstract

Decoding Protein-protein Interactions: An Overview

Cited by 17 publications

References 287 publications

Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode

Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode

Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing

Mechanism of ligusticum cycloprolactam against neuroinflammation based on network pharmacology and experimental verification

Contact Info

Product

Resources

About