scholarly journals Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2596
Author(s):  
Lisha Wang ◽  
Liza Bergkvist ◽  
Rajnish Kumar ◽  
Bengt Winblad ◽  
Pavel F. Pavlov
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Protein Interactions ◽  
Intracellular Transport ◽  
Atp Hydrolysis ◽  
Specific Protein ◽  
Future Perspective ◽  
Protein Protein Interactions ◽  
Novel Approach ◽  
Chaperone Interactions

The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein–protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.

scholarly journals Small molecules inhibiting Keap1–Nrf2 protein–protein interactions: a novel approach to activate Nrf2 function

MedChemComm ◽  
2017 ◽  
Vol 8 (2) ◽  
pp. 286-294 ◽  
Author(s):  
Chunlin Zhuang ◽  
Zhongli Wu ◽  
Chengguo Xing ◽  
Zhenyuan Miao
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Small Molecule Inhibition ◽  
Novel Approach ◽  
Nrf2 Protein

Small-molecule inhibition of Keap1–Nrf2 protein–protein interactions as a novel approach to activate Nrf2.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

scholarly journals Theoretical models of inhibitory activity for inhibitors of protein–protein interactions: targeting menin–mixed lineage leukemia with small molecules

MedChemComm ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 2216-2227 ◽  
Author(s):  
Wiktoria Jedwabny ◽  
Szymon Kłossowski ◽  
Trupta Purohit ◽  
Tomasz Cierpicki ◽  
Jolanta Grembecka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Empirical Model ◽  
Inhibitory Activity ◽  
Theoretical Models ◽  
Mixed Lineage Leukemia ◽  
Protein Protein Interactions ◽  
Model Based ◽  
Dispersion Terms

A computationally affordable, non-empirical model based on electrostatic multipole and dispersion terms successfully predicts the binding affinity of inhibitors of menin–MLL protein–protein interactions.

Metallocluster transactions: dynamic protein interactions guide the biosynthesis of Fe–S clusters in bacteria

2018 ◽  
Vol 46 (6) ◽  
pp. 1593-1603 ◽  
Author(s):  
Chenkang Zheng ◽  
Patricia C. Dos Santos
Keyword(s):  
Protein Interactions ◽  
Protein Complexes ◽  
Specific Protein ◽  
Biological Synthesis ◽  
Cluster Assembly ◽  
Sequence Motifs ◽  
Protein Protein Interactions ◽  
Cysteine Desulfurase ◽  
Wide Range ◽  
Domains Of Life

Iron–sulfur (Fe–S) clusters are ubiquitous cofactors present in all domains of life. The chemistries catalyzed by these inorganic cofactors are diverse and their associated enzymes are involved in many cellular processes. Despite the wide range of structures reported for Fe–S clusters inserted into proteins, the biological synthesis of all Fe–S clusters starts with the assembly of simple units of 2Fe–2S and 4Fe–4S clusters. Several systems have been associated with the formation of Fe–S clusters in bacteria with varying phylogenetic origins and number of biosynthetic and regulatory components. All systems, however, construct Fe–S clusters through a similar biosynthetic scheme involving three main steps: (1) sulfur activation by a cysteine desulfurase, (2) cluster assembly by a scaffold protein, and (3) guided delivery of Fe–S units to either final acceptors or biosynthetic enzymes involved in the formation of complex metalloclusters. Another unifying feature on the biological formation of Fe–S clusters in bacteria is that these systems are tightly regulated by a network of protein interactions. Thus, the formation of transient protein complexes among biosynthetic components allows for the direct transfer of reactive sulfur and Fe–S intermediates preventing oxygen damage and reactions with non-physiological targets. Recent studies revealed the importance of reciprocal signature sequence motifs that enable specific protein–protein interactions and consequently guide the transactions between physiological donors and acceptors. Such findings provide insights into strategies used by bacteria to regulate the flow of reactive intermediates and provide protein barcodes to uncover yet-unidentified cellular components involved in Fe–S metabolism.

scholarly journals Bi-directional protein-protein interactions control liquid-liquid phase separation of PSD-95 and its interaction partners

2021 ◽  
Author(s):  
Nikolaj Riis Christensen ◽  
Christian Parsbæk Pedersen ◽  
Vita Sereikaite ◽  
Jannik Nedergaard Pedersen ◽  
Maria Vistrup-Parry ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Protein Interactions ◽  
Postsynaptic Density ◽  
Specific Protein ◽  
Liquid Phase Separation ◽  
Protein Protein Interactions ◽  
New Perspective ◽  
Liquid Liquid Phase Separation

SUMMARYThe organization of the postsynaptic density (PSD), a protein-dense semi-membraneless organelle, is mediated by numerous specific protein-protein interactions (PPIs) which constitute a functional post-synapse. Postsynaptic density protein 95 (PSD-95) interacts with a manifold of proteins, including the C-terminal of transmembrane AMPA receptor (AMAPR) regulatory proteins (TARPs). Here, we uncover the minimal essential peptide responsible for the stargazin (TARP-γ2) mediated liquid-liquid phase separation (LLPS) formation of PSD-95 and other key protein constituents of the PSD. Furthermore, we find that pharmacological inhibitors of PSD-95 can facilitate formation of LLPS. We found that in some cases LLPS formation is dependent on multivalent interactions while in other cases short peptides carrying a high charge are sufficient to promote LLPS in complex systems. This study offers a new perspective on PSD-95 interactions and their role in LLPS formation, while also considering the role of affinity over multivalency in LLPS systems.

Small Molecules Targeting Protein–Protein Interactions: A Promising Anti-HIV Strategy

2010 ◽  
Vol 86 (1) ◽  
pp. A32
Author(s):  
Alba Chimirri ◽  
Laura De Luca ◽  
Stefania Ferro ◽  
Rosaria Gitto ◽  
Anna Maria Monforte ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Anti Hiv

Protein Interactions for Functional Genomics

2012 ◽  
Vol 3 (4) ◽  
pp. 15-30
Author(s):  
Pablo Minguez ◽  
Joaquin Dopazo
Keyword(s):  
Graph Theory ◽  
Protein Interactions ◽  
Biological Networks ◽  
State Of The Art ◽  
Protein Protein Interactions ◽  
Pairwise Interactions ◽  
Novel Approach ◽  
Functional Profiling ◽  
Available Resources

Here the authors review the state of the art in the use of protein-protein interactions (ppis) within the context of the interpretation of genomic experiments. They report the available resources and methodologies used to create a curated compilation of ppis introducing a novel approach to filter interactions. Special attention is paid in the complexity of the topology of the networks formed by proteins (nodes) and pairwise interactions (edges). These networks can be studied using graph theory and a brief introduction to the characterization of biological networks and definitions of the more used network parameters is also given. Also a report on the available resources to perform different modes of functional profiling using ppi data is provided along with a discussion on the approaches that have typically been applied into this context. They also introduce a novel methodology for the evaluation of networks and some examples of its application.

scholarly journals Coevolution-based prediction of protein–protein interactions in polyketide biosynthetic assembly lines

2020 ◽  
Vol 36 (19) ◽  
pp. 4846-4853 ◽  
Author(s):  
Yan Wang ◽  
Miguel Correa Marrero ◽  
Marnix H Medema ◽  
Aalt D J van Dijk
Keyword(s):  
Protein Interactions ◽  
Antitumor Agents ◽  
Acyl Carrier Protein ◽  
Specific Protein ◽  
Combinatorial Biosynthesis ◽  
Supplementary Information ◽  
Protein Protein Interactions ◽  
Assembly Lines ◽  
Specific Order ◽  
Encoding Genes

Abstract Motivation Polyketide synthases (PKSs) are enzymes that generate diverse molecules of great pharmaceutical importance, including a range of clinically used antimicrobials and antitumor agents. Many polyketides are synthesized by cis-AT modular PKSs, which are organized in assembly lines, in which multiple enzymes line up in a specific order. This order is defined by specific protein–protein interactions (PPIs). The unique modular structure and catalyzing mechanism of these assembly lines makes their products predictable and also spurred combinatorial biosynthesis studies to produce novel polyketides using synthetic biology. However, predicting the interactions of PKSs, and thereby inferring the order of their assembly line, is still challenging, especially for cases in which this order is not reflected by the ordering of the PKS-encoding genes in the genome. Results Here, we introduce PKSpop, which uses a coevolution-based PPI algorithm to infer protein order in PKS assembly lines. Our method accurately predicts protein orders (93% accuracy). Additionally, we identify new residue pairs that are key in determining interaction specificity, and show that coevolution of N- and C-terminal docking domains of PKSs is significantly more predictive for PPIs than coevolution between ketosynthase and acyl carrier protein domains. Availability and implementation The code is available on http://www.bif.wur.nl/ (under ‘Software’). Supplementary information Supplementary data are available at Bioinformatics online.

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