Chapter 4: Protein Function

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4.2:

Interfacce proteina-proteina

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Molecular Biology

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JoVE Core Molecular Biology

Protein-protein Interfaces

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4.1: Ligand Binding Sites

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4.3: Conserved Binding Sites

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molti processi biologici dipendono dalle interazioni proteine-proteine. La maggior parte delle proteine, infatti, ha bisogno di formare complessi proteici, o oligomeri, per svolgere le proprie funzioni. A volte due o più proteine identiche formano un complesso, come la chinesina, dimero, che consiste di due catene proteiche identiche.In altri casi, differenti proteine o polipeptidi si uniscono per formare un’unità funzionale. Ad esempio, i microtubuli citoscheletrici sono costituiti da dimeri di alfa e beta tubulina. Le superfici leganti dei monomeri alfa e beta tubulinici hanno forme complementari.Sono forme di adattamento che consentono ai monomeri di formare un gran numero di interazioni non covalenti, che servono a tenere insieme l’alfa e la beta tubulina. Questo tipo di interfaccia è un esempio di un’interazione superficie-superficie. Simili ai siti di legame del ligando, le interazioni ad un’interfaccia proteina-proteina possono implicare legami non covalenti e forze idrofobiche;tuttavia, i legami disolfuro covalenti tra gli amminoacidi di cisteina su ogni superficie della proteina possono anche giocare il ruolo di mantenerli insieme.Non tutte le interfacce proteiche coinvolgono strettamente le superfici di corrispondenza, per esempio, molti enzimi, come la protein chinasi A, formano un’apertura che può riconoscere e legare le anse polipeptidiche dei loro partner di legame. questo tipo di interfaccia è nota come interazione superficie-stringa. Un altro tipo di interfaccia, nota come interazione elica-elica o doppia spirale, si forma quando le eliche di due proteine si avvolgono l’una intorno all’altra;questa interfaccia è osservata frequentemente in proteine che contengono domini di cerniera di leucine, come fattori di trascrizione eucariotici.In conclusione, la struttura fisica e le proprietà chimiche delle parti interagenti, determinano il tipo di interfaccia tra due proteine.

4.2:

Interfacce proteina-proteina

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 polypeptide chain or string.

Various computational and biochemical methods are used to study protein interfaces. Laboratory methods, such as affinity purification, mass spectrometry, and protein microarrays, can be used to identify new interactions. Co-immunoprecipitation of proteins and yeast two-hybrid screening are widely used to provide evidence on whether two proteins interact in vitro. Computer programs can predict PPIs based on similar interactions found in other proteins by comparing protein sequences and three-dimensional structures. Other computational approaches, such as phylogenetic profiling, predict PPIs based on the coevolution of binding partners. Additionally, gene fusion analysis is used to predict interaction partners by finding protein pairs that are fused in the genome of other organisms.

Proteins typically interact with multiple partners either at the same or different times, and they may contain more than one interaction interface. Many proteins form large complexes that perform specific functions that can only be carried out by the complete complex. In some cases, these protein interactions are regulated; that is, a protein may interact with different partners based on cellular needs. Further computational and statistical analyses sort such interactions into networks, which are curated in online interactome databases. These searchable databases enable users to study specific protein interactions, as well as design drugs that can enhance or disrupt interactions at the interface.

Suggested Reading

Koh GC, Porras P, Aranda B, Hermjakob H, Orchard SE. Analyzing protein-protein interaction networks. Journal of Proteome Research. 2012 Apr;11(4):2014-2031.
Laraia L, McKenzie G, Spring DR, Venkitaraman AR, Huggins DJ. Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions. Chem Biol. 2015;22(6):689–703.
De Las Rivas J, Fontanillo C. Protein-protein interactions essentials: key concepts to building and analyzing interactome networks. PLoS Comput Biol. 2010;6(6):e1000807.
Lalonde S, Ehrhardt DW, Loqué D, Chen J, Rhee SY, Frommer WB. Molecular and cellular approaches for the detection of protein-protein interactions: latest techniques and current limitations. Plant J. 2008 Feb;53(4):610-35.
Amos-Binks A, Patulea C, Pitre S, et al. Binding site prediction for protein-protein interactions and novel motif discovery using re-occurring polypeptide sequences. BMC Bioinformatics. 2011;12:225. Published 2011 Jun 2.

Tags

Protein-protein Interfaces Protein Complexes Oligomers Kinesin Dimer Cytoskeletal Microtubules Alpha-tubulin Beta-tubulin Non-covalent Bonds Surface-surface Interaction Ligand Binding Sites Hydrophobic Forces Covalent Disulfide Bonds Protein Kinase A Cleft Polypeptide Loops Surface-string Interaction Helix-helix Interaction Coiled-coil Interaction