Related Experiment Video
Updated: Jun 10, 2025
06:50
Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions
Published on: January 26, 2024
1.7K
The genetic architecture of protein interaction affinity and specificity
Alexandra M Bendel1,2,3, Andre J Faure4,5, Dominique Klein1
1Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
Nature Communications
|October 14, 2024
Summary
Most mutations affect protein binding affinity broadly, while rare mutations alter specificity. Specificity arises from residues promoting on-target and preventing off-target interactions, revealing distributed encoding in protein families.
Area of Science:
- Molecular Biology
- Biophysics
- Genetics
Background:
- Understanding protein-protein interactions (PPIs) is crucial for deciphering biological processes.
- The evolutionary mechanisms governing specificity and affinity in PPIs remain largely unknown.
- Basic leucine zipper (bZIP) transcription factors represent a large family with diverse interaction partners.
Purpose of the Study:
- To quantify the impact of all possible mutations in the JUN protein on its binding affinity and specificity towards all 54 human bZIP transcription factors.
- To elucidate the molecular basis of how mutations affect both affinity and specificity in a large protein family.
- To investigate the role of distributed residues within the interaction interface in determining binding characteristics.
Main Methods:
- Comprehensive mutagenesis of the JUN protein.
- Quantitative measurement of binding affinity and specificity across all 54 human bZIP partners.
- Global thermodynamic modeling to analyze mutation effects.
- Analysis of residue distribution within the interaction interface.
Main Results:
- The majority of mutations altered JUN's affinity uniformly across all binding partners.
- Mutations affecting binding specificity were infrequent but located throughout the interaction interface.
- Specificity-determining residues often played dual roles in promoting on-target and preventing off-target binding.
- Interface mutations altering specificity were largely pleiotropic, also affecting affinity.
- Mutations outside the interface could modulate global affinity without impacting specificity.
Conclusions:
- Specificity and affinity in PPIs are encoded in a distributed manner across the interaction interface.
- Coiled-coil structures offer an effective mechanism for optimizing both specificity and affinity in large protein families.
- The study provides insights into the evolutionary strategies for generating diverse yet specific protein interactions.
More Related Videos
07:08Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
7.2K
08:38Genome-wide Protein-protein Interaction Screening by Protein-fragment Complementation Assay PCA in Living Cells
Published on: March 3, 2015
13.3K
Related Concept Videos
02:26Protein Networks
3.9K
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
3.9K
02:04Protein-protein Interfaces
12.5K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
12.5K
01:49Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K
02:40Ligand Binding Sites
12.8K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.8K
01:57Protein Complexes with Interchangeable Parts
2.5K
Groups of proteins may form a complex where each protein in this complex has a different role in the overall execution of the complex’s function. Often some of the proteins in the complex can be replaced by a closely related variant to give a complex that contains many of the same components yet is functionally distinct.
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
2.5K
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K