Binding Hot Spots in the TEM1–BLIP Interface in Light of its Modular Architecture

Reichmann, Dana; Cohen, Marion C.; Abramovich, Renne; Dym, Orly; Lim, Daniel; Strynadka, N.C.J.; Schreiber, Gideon

doi:10.1016/j.jmb.2006.09.076

Cited by 82 publications

(116 citation statements)

References 44 publications

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“…Colored dots above GLD-3 KH domains highlight residues involved in intramolecular interactions with another KH domain (colors as above) or with the N-terminal and C-terminal segments present in the construct used (blue and black dots, respectively). The interacting residues were identified with the program AquaProt (Reichmann et al 2007). The C-terminal segment present in the structure downstream from KH5 is not shown in the alignment.…”

Section: Resultsmentioning

confidence: 99%

Four KH domains of the C. elegans Bicaudal-C ortholog GLD-3 form a globular structural platform

Nakel¹,

Hartung²,

Bonneau³

et al. 2010

RNA

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Caenorhabditis elegans GLD-3 is a five K homology (KH) domain-containing protein involved in the translational control of germline-specific mRNAs during embryogenesis. GLD-3 interacts with the cytoplasmic poly(A)-polymerase GLD-2. The two proteins cooperate to recognize target mRNAs and convert them into a polyadenylated, translationally active state. We report the 2.8-Å -resolution crystal structure of a proteolytically stable fragment encompassing the KH2, KH3, KH4, and KH5 domains of C. elegans GLD-3. The structure reveals that the four tandem KH domains are organized into a globular structural unit. The domains are involved in extensive side-by-side interactions, similar to those observed in previous structures of dimeric KH domains, as well as head-to-toe interactions. Small-angle X-ray scattering reconstructions show that the N-terminal KH domain (KH1) forms a thumb-like protrusion on the KH2-KH5 unit. Although KH domains are putative RNA-binding modules, the KH region of GLD-3 is unable in isolation to cross-link RNA. Instead, the KH1 domain mediates the direct interaction with the poly(A)-polymerase GLD-2, pointing to a function of the KH region as a protein-protein interaction platform.

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Section: Resultsmentioning

confidence: 99%

Four KH domains of the C. elegans Bicaudal-C ortholog GLD-3 form a globular structural platform

Nakel¹,

Hartung²,

Bonneau³

et al. 2010

RNA

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“…Dotted lines represent extended/loop regions. Above the sequences, colored circles highlight the residues involved in the interaction with Cup (orange), and eIF4E (purple-blue) as identified using the AquaProt server (Reichmann et al 2007). Other interactions known from previous structural studies are indicated as colored empty circles above the sequences: interactions with eIF4G (dark green), m 7 GTP (black), and 4E-BP (light green) (Marcotrigiano et al 1997(Marcotrigiano et al , 1999Matsuo et al 1997;Gross et al 2003).…”

Section: Structure Determination and Qualitymentioning

confidence: 99%

Crystal structure of a minimal eIF4E–Cup complex reveals a general mechanism of eIF4E regulation in translational repression

Kinkelin

Veith

Grünwald

et al. 2012

RNA

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Cup is an eIF4E-binding protein (4E-BP) that plays a central role in translational regulation of localized mRNAs during early Drosophila development. In particular, Cup is required for repressing translation of the maternally contributed oskar, nanos, and gurken mRNAs, all of which are essential for embryonic body axis determination. Here, we present the 2.8 Å resolution crystal structure of a minimal eIF4E-Cup assembly, consisting of the interacting regions of the two proteins. In the structure, two separate segments of Cup contact two orthogonal faces of eIF4E. The eIF4E-binding consensus motif of Cup (YXXXXLF) binds the convex side of eIF4E similarly to the consensus of other eIF4E-binding proteins, such as 4E-BPs and eIF4G. The second, noncanonical, eIF4E-binding site of Cup binds laterally and perpendicularly to the eIF4E b-sheet. Mutations of Cup at this binding site were shown to reduce binding to eIF4E and to promote the destabilization of the associated mRNA. Comparison with the binding mode of eIF4G to eIF4E suggests that Cup and eIF4G binding would be mutually exclusive at both binding sites. This shows how a common molecular surface of eIF4E might recognize different proteins acting at different times in the same pathway. The structure provides insight into the mechanism by which Cup disrupts eIF4E-eIF4G interaction and has broader implications for understanding the role of 4E-BPs in translational regulation.

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“…[17]). Furthermore, sequence and structural plasticity of binding sites could facilitate interaction with several protein partners [18]. The nature and distribution of binding hot spots also play an important role in protein associations.…”

Section: Introductionmentioning

confidence: 99%

Energetic determinants of protein binding specificity: Insights into protein interaction networks

2009

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One of the challenges of the postgenomic era is to provide a more realistic representation of cellular processes by combining a systems biology description of functional networks with information on their interacting components. Here we carried out a systematic large-scale computational study on a structural protein-protein interaction network dataset in order to dissect thermodynamic characteristics of binding determining the interplay between protein affinity and specificity. As expected, interactions involving specific binding sites display higher affinities than those of promiscuous binding sites. Next, in order to investigate a possible role of modular distribution of hot spots in binding specificity, we divided binding sites into modules previously shown to be energetically independent. In general, hot spots that interact with different partners are located in different modules. We further observed that common hot spots tend to interact with partners exhibiting common binding motifs, whereas different hot spots tend to interact with partners with different motifs. Thus, energetic properties of binding sites provide insights into the way proteins modulate interactions with different partners. Knowledge of those factors playing a role in protein specificity is important for understanding how proteins acquire additional partners during evolution. It should also be useful in drug design.

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Binding Hot Spots in the TEM1–BLIP Interface in Light of its Modular Architecture

Cited by 82 publications

References 44 publications

Four KH domains of the C. elegans Bicaudal-C ortholog GLD-3 form a globular structural platform

Four KH domains of the C. elegans Bicaudal-C ortholog GLD-3 form a globular structural platform

Crystal structure of a minimal eIF4E–Cup complex reveals a general mechanism of eIF4E regulation in translational repression

Energetic determinants of protein binding specificity: Insights into protein interaction networks

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