Principles of protein-protein interactions.

Jones, Susan R.; Thornton, Janet M.

doi:10.1073/pnas.93.1.13

Cited by 2,485 publications

(2,014 citation statements)

References 48 publications

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“…Consistent with this notion, the stability of the early intermediate and the rate of stable complex assembly have a strong dependence on ionic strength (32). Critical roles of electrostatic interactions in enhancing protein interaction kinetics have been predicted theoretically (33,34) and demonstrated in multiple cases (35)(36)(37)(38); our results further emphasize the role of such interactions in stabilizing assembly intermediates, which provides an effective way to accelerate the overall assembly process.…”

Section: Discussionsupporting

confidence: 71%

Direct Visualization Reveals Dynamics of a Transient Intermediate During Protein Assembly

Zhang¹

2011

Multistate GTPase Control Co-Translational Protein Targeting

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Interactions between proteins underlie numerous biological functions. Theoretical work suggests that protein interactions initiate with formation of transient intermediates that subsequently relax to specific, stable complexes. However, the nature and roles of these transient intermediates have remained elusive. Here, we characterized the global structure, dynamics, and stability of a transient, on-pathway intermediate during complex assembly between the Signal Recognition Particle (SRP) and its receptor. We show that this intermediate has overlapping but distinct interaction interfaces from that of the final complex, and it is stabilized by longrange electrostatic interactions. A wide distribution of conformations is explored by the intermediate; this distribution becomes more restricted in the final complex and is further regulated by the cargo of SRP. These results suggest a funnel-shaped energy landscape for protein interactions, and they provide a framework for understanding the role of transient intermediates in protein assembly and biological regulation.EPR spectroscopy | fluorescence spectroscopy | molecular recognition | protein targeting | GTPases I nteractions between proteins are central to biology and underlie numerous molecular recognition, regulation, and signaling events (1). A challenge in our understanding of protein interactions is to reconcile their fast association kinetics required for biological function (10 6 -10 8 M −1 s −1 ) with the fact that formation of stable protein assemblies often involves extensive short-range, stereospecific interactions that are difficult to accomplish during a single diffusional encounter (2-4). This problem becomes more pronounced in protein interactions that require extensive conformational changes in the interaction partners. Much theoretical work has suggested that assembly of a protein complex initiates with the formation of a transient intermediate held together by solvent cage and long-range electrostatic attractions, followed by relative rotatory diffusions of the binding partners to search for the optimal interaction interface with shape and electrostatic complementarity (4-9). An extreme example of this concept is the "fly-casting mechanism," in which unstructured protein molecules bind targets weakly at a relatively large distance followed by folding at the target site (10-12). In general, formation of transient intermediates reduces the dimension of translational and rotational search and could significantly accelerate protein association.Despite significant progress in theoretical work, direct experimental demonstration of this model has been limited, and the structural and dynamic nature of transient intermediates during protein interactions has remained elusive. Experimental studies of transient intermediates are still at the infant stage, because these intermediates have short lifetimes and are rarely populated at equilibrium. Pioneering NMR studies have revealed the structures of rare conformational states in equilibrium with the predominant ...

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Section: Discussionsupporting

confidence: 71%

Direct Visualization Reveals Dynamics of a Transient Intermediate During Protein Assembly

Zhang¹

2011

Multistate GTPase Control Co-Translational Protein Targeting

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“…Comparison between epitopes and other types of proteinprotein interfaces in transient hetero-complexes with respect to physico-chemical and structural characteristics (Bogan and Thorn, 1998;Jones and Thornton, 1995, 1996, 1997aNeuvirth et al, 2004), revealed general similarities between the two types of protein regions. Namely, preference for tyrosine and tryptophan residue and unorganized secondary structures was found to characterize both types of interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Although the amount of antibody-antigen co-crystal data remained limited, these analyses revealed general principles of protein-protein interactions, which also had implications for antibody-antigen interactions. Jones and Thornton (1995, 1996, 1997a compared interfaces and non-interface regions with respect to physico-chemical and structural properties at the amino acid level, such as ASA, amino acid composition, degree of protrusion, and flexibility.…”

Section: Introductionmentioning

confidence: 99%

Computational characterization of B-cell epitopes

Rubinstein

Mayrose

Halperin

et al. 2008

Molecular Immunology

210

232

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Characterizing B-cell epitopes is a fundamental step for understanding the immunological basis of bio-recognition. To date, epitope analyses have either been based on limited structural data, or sequence data alone. In this study, our null hypothesis was that the surface of the antigen is homogeneously antigenic. To test this hypothesis, a large dataset of antibody-antigen complex structures, together with crystal structures of the native antigens, has been compiled. Computational methods were developed and applied to detect and extract physico-chemical, structural, and geometrical properties that may distinguish an epitope from the remaining antigen surface. Rigorous statistical inference was able to clearly reject the null hypothesis showing that epitopes are distinguished from the remaining antigen surface in properties such as amino acid preference, secondary structure composition, geometrical shape, and evolutionary conservation. Specifically, epitopes were found to be significantly enriched with tyrosine and tryptophan, and to show a general preference for charged and polar amino acids. Additionally, epitopes were found to show clear preference for residing on planar parts of the antigen that protrude from the surface, yet with a rugged surface shape at the atom level. The effects of complex formation on the structural properties of the antigen were also computationally characterized and it is shown that epitopes undergo compression upon antibody binding. This correlates with the finding that epitopes are enriched with unorganized secondary structure elements that render them flexible. Thus, this study extends the understanding of the underlying processes required for antibody binding, and reveals new aspects of the antibody-antigen interaction.

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“…uk/bsm/PP/server/index.html) (Jones and Thornton 1996), is 1159 Å 2 . How does this value compare to that of a typical crystal contact interface?…”

Section: Analysis Of the Crystal Packing Of Thioredoxin Mmentioning

confidence: 99%