Linear Motif-Mediated Interactions Have Contributed to the Evolution of Modularity in Complex Protein Interaction Networks

Kim, Inhae; Lee, Heetak; Han, Seong Kyu; Kim, Sanguk

doi:10.1371/journal.pcbi.1003881

Cited by 16 publications

(25 citation statements)

References 62 publications

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“…The ability of IDPs to form numerous complexes also has significant consequences for proteome interconnectivity. ID segments tend to connect functional modules, thereby interweaving disparate parts of PPI networks . Within proteomes, the ID segments of proteins frequently contain the actual interacting regions, and interactions between wholly disordered proteins are enriched in the human PPI network …”

Section: Formation Of Protein Complexes and Assembliesmentioning

confidence: 99%

“…ID segments tend to connect functional modules, thereby interweaving disparate parts of PPI networks. 48,73 Within proteomes, the ID segments of proteins frequently contain the actual interacting regions, 74 and interactions between wholly disordered proteins are enriched in the human PPI network. 75 Importantly, due to the small number of residues that frequently make an interaction site in IDRs, functional sites can be more easily disrupted by mutations.…”

Section: Idps Can Lead To Promiscuous Interactions In Cells Duementioning

confidence: 99%

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How do disordered regions achieve comparable functions to structured domains?

et al. 2015

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The traditional structure to function paradigm conceives of a protein's function as emerging from its structure. In recent years, it has been established that unstructured, intrinsically disordered regions (IDRs) in proteins are equally crucial elements for protein function, regulation and homeostasis. In this review, we provide a brief overview of how IDRs can perform similar functions to structured proteins, focusing especially on the formation of protein complexes and assemblies and the mediation of regulated conformational changes. In addition to highlighting instances of such functional equivalence, we explain how differences in the biological and physicochemical properties of IDRs allow them to expand the functional and regulatory repertoire of proteins. We also discuss studies that provide insights into how mutations within functional regions of IDRs can lead to human diseases.

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Section: Formation Of Protein Complexes and Assembliesmentioning

confidence: 99%

Section: Idps Can Lead To Promiscuous Interactions In Cells Duementioning

confidence: 99%

How do disordered regions achieve comparable functions to structured domains?

et al. 2015

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“…We summarized statistics for such networks in Supplementary Table S1. We used 12,207 pairs of interacting domains that had been identified by either 3D structures of protein complexes or various prediction methods 21,22 . We applied this approach to 15 PPI networks and generated 15 sets To construct domain-resolved protein interaction networks (DPNs), species-specific protein interaction networks (e.g., BIOGRID network in humans), domain annotations, and reference domain interactions were used (left).…”

Section: Resultsmentioning

confidence: 99%

“…Domain-mediated interactions contain both domain-domain interactions (DDIs) and domain-linear motif interactions (DLIs). In particular, DLIs are crucial for fine regulation of signaling pathways and for connecting two different functional modules 21 . Although DLIs are critical for understanding biological processes, we consider only DDIs because of limitations in the accuracy of DLI datasets and linear motif annotations.…”

Section: Discussionmentioning

confidence: 99%

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Domain-mediated interactions for protein subfamily identification

Lee¹,

Kim²,

Han³

et al. 2020

Sci Rep

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Within a protein family, proteins with the same domain often exhibit different cellular functions, despite the shared evolutionary history and molecular function of the domain. We hypothesized that domain-mediated interactions (DMis) may categorize a protein family into subfamilies because the diversified functions of a single domain often depend on interacting partners of domains. Here we systematically identified DMI subfamilies, in which proteins share domains with DMI partners, as well as with various functional and physical interaction networks in individual species. in humans, DMi subfamily members are associated with similar diseases, including cancers, and are frequently co-associated with the same diseases. DMi information relates to the functional and evolutionary subdivisions of human kinases. in yeast, DMi subfamilies contain proteins with similar phenotypic outcomes from specific chemical treatments. Therefore, the systematic investigation here provides insights into the diverse functions of subfamilies derived from a protein family with a link-centric approach and suggests a useful resource for annotating the functions and phenotypic outcomes of proteins.Protein families consist of evolutionarily, functionally, and structurally relevant proteins 1 , which provide insights into protein functions and the relationship between genes and phenotypes 2-6 . Protein subfamilies emerged to divide protein families into subgroups of diversified molecular functions; hence, each subfamily includes functionally more similar proteins. Many previous studies, including subfamily classifications in phylogenomics (SCI-PHY) 7 , Genome Modeling and Model Annotation (GeMMA) 8 , Active Sites Modeling and Clustering (ASMC) 9 , Two-Level Iterative Clustering Process (TuLIP) 10 , and Signature Dynamics of Protein Families (SignDy) 11 , utilize the similarity between proteins based on sequence, structure, or dynamics to identify protein subfamilies. As a result of previous classification methods, the functionally relevant proteins within the same subfamily tend to have similar structures and sequences, which may mediate distinct protein interactions across subfamilies within the same protein family 12 .Here, we propose that particular domain-mediated interactions (DMIs) subdivide a protein family into its subfamilies consisting of biologically relevant proteins. Indeed, functional activities of proteins are closely associated with processes in which interacting proteins are involved 13,14 . For instance, although Pho85 and Bck1 are single-domain proteins and both possess a Pkinase domain (Pfam-A, PF00069), Pho85 interacts with Pcl1 (cyclin) and acts in the cell cycle mechanism, whereas Bck1 interacts with and activates Mkk2 (mitogen-activated kinase kinase) in a cell wall modulation pathway in yeast 15,16 . Similarly, changes in a shared domain across proteins within the same protein family mediate the divergence of interactions 17 . Furthermore, the interacting proteins in a domain-domain interaction are known to co-evolve 18...

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The influence of intrinsic folding mechanism of an unfolded protein on the coupled folding‐binding process during target recognition

et al. 2018

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Intrinsically disordered proteins (IDPs) are extensively involved in dynamic signaling processes which require a high association rate and a high dissociation rate for rapid binding/unbinding events and at the same time a sufficient high affinity for specific recognition. Although the coupled folding‐binding processes of IDPs have been extensively studied, it is still impossible to predict whether an unfolded protein is suitable for molecular signaling via coupled folding‐binding. In this work, we studied the interplay between intrinsic folding mechanisms and coupled folding‐binding process for unfolded proteins through molecular dynamics simulations. We first studied the folding process of three representative IDPs with different folded structures, that is, c‐Myb, AF9, and E3 rRNase. We found the folding free energy landscapes of IDPs are downhill or show low barriers. To further study the influence of intrinsic folding mechanism on the binding process, we modulated the folding mechanism of barnase via circular permutation and simulated the coupled folding‐binding process between unfolded barnase permutant and folded barstar. Although folding of barnase was coupled to target binding, the binding kinetics was significantly affected by the intrinsic folding free energy barrier, where reducing the folding free energy barrier enhances binding rate up to two orders of magnitude. This accelerating effect is different from previous results which reflect the effect of structure flexibility on binding kinetics. Our results suggest that coupling the folding of an unfolded protein with no/low folding free energy barrier with its target binding may provide a way to achieve high specificity and rapid binding/unbinding kinetics simultaneously.

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Linear Motif-Mediated Interactions Have Contributed to the Evolution of Modularity in Complex Protein Interaction Networks

Cited by 16 publications

References 62 publications

How do disordered regions achieve comparable functions to structured domains?

How do disordered regions achieve comparable functions to structured domains?

Domain-mediated interactions for protein subfamily identification

The influence of intrinsic folding mechanism of an unfolded protein on the coupled folding‐binding process during target recognition

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