Protein-protein Interfaces

Protein-protein interfaces fall into three main types. Surface-surface interactions occur when complementary protein shapes form numerous non-covalent bonds, as seen in alpha- and beta-tubulin dimers. Surface-string interactions form when enzymes like protein kinase A create clefts that recognize polypeptide loops. Helix-helix or coiled-coil interactions develop when protein helices wrap around each other, commonly found in transcription factors with leucine zipper domains.

Most protein-protein interactions are stabilized by numerous weak noncovalent chemical forces, including hydrogen bonds and hydrophobic interactions. Additionally, covalent disulfide bonds between cysteine amino acids on protein surfaces may strengthen interactions. The physical structure and chemical properties of the interacting parts determine which stabilization mechanisms operate at each interface.

Many proteins form complexes because they need to work together to carry out their functions. A large number of proteins cannot perform their biological roles as individual molecules. For example, cytoskeletal microtubules consist of alpha- and beta-tubulin dimers, and many enzymes require binding partners to achieve their catalytic function. These protein complexes are essential for an organism's survival.

Laboratory methods such as affinity purification, mass spectrometry, and protein microarrays identify new interactions. Co-immunoprecipitation and yeast two-hybrid screening provide evidence of whether two proteins interact in vitro. These biochemical approaches are complemented by computational methods that predict interactions based on protein sequences, three-dimensional structures, and coevolution patterns of binding partners.

Computer programs predict protein-protein interactions by comparing protein sequences and three-dimensional structures to identify similar interactions in other proteins. Phylogenetic profiling predicts interactions based on the coevolution of binding partners across species. Gene fusion analysis identifies interaction partners by finding protein pairs that are fused in the genomes of other organisms, revealing functional relationships.

Proteins typically interact with multiple partners either simultaneously or at different times, and many contain more than one interaction interface. In some cases, protein interactions are regulated, meaning a protein may interact with different partners based on cellular needs. These interactions are organized into networks and curated in online interactome databases, enabling researchers to study specific interactions and design drugs that enhance or disrupt them.

The physical shape of protein interfaces and their chemical properties determine how two proteins interact. Globular proteins with closely-matching surface shapes form large numbers of weak bonds through surface-surface interactions. Conversely, proteins with clefts or helical structures engage in surface-string or helix-helix interactions. These structural and chemical features dictate which binding mechanisms and stabilization forces operate at each protein-protein interface.