Dataset Information

Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores.

ABSTRACT: Since publication of the crystal structure of protein kinase (PK)A three decades ago, a structural portrait of the conserved kinase core has been drawn. The next challenge is to elucidate structures of full-length kinases and to address the intrinsically disordered regions (IDRs) that typically flank the core as well as the small linear motifs (SLiMs) that are embedded within the IDRs. It is increasingly apparent that unstructured regions integrate the kinase catalytic chassis into multienzyme-based regulatory networks. The extracellular signal-regulated kinase-ribosomal S6 PK-phosphoinositide-dependent kinase (ERK-RSK-PDK) complex is an excellent example to demonstrate how IDRs and SLiMs govern communication between four different kinase catalytic cores to mediate activation and how in molecular terms these promote the formation of kinase heterodimers in a context dependent fashion.

SUBMITTER: Gogl G

PROVIDER: S-EPMC6592696 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores.

Gógl Gergő G Kornev Alexandr P AP Reményi Attila A Taylor Susan S SS

Trends in biochemical sciences 20190102 4

Since publication of the crystal structure of protein kinase (PK)A three decades ago, a structural portrait of the conserved kinase core has been drawn. The next challenge is to elucidate structures of full-length kinases and to address the intrinsically disordered regions (IDRs) that typically flank the core as well as the small linear motifs (SLiMs) that are embedded within the IDRs. It is increasingly apparent that unstructured regions integrate the kinase catalytic chassis into multienzyme-b ...[more]

PMID: 30611608

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Project description:Many disordered proteins function via binding to a structured partner and undergo a disorder-to-order transition. The coupled folding and binding can confer several functional advantages such as the precise control of binding specificity without increased affinity. Additionally, the inherent flexibility allows the binding site to adopt various conformations and to bind to multiple partners. These features explain the prevalence of such binding elements in signaling and regulatory processes. In this work, we report ANCHOR, a method for the prediction of disordered binding regions. ANCHOR relies on the pairwise energy estimation approach that is the basis of IUPred, a previous general disorder prediction method. In order to predict disordered binding regions, we seek to identify segments that are in disordered regions, cannot form enough favorable intrachain interactions to fold on their own, and are likely to gain stabilizing energy by interacting with a globular protein partner. The performance of ANCHOR was found to be largely independent from the amino acid composition and adopted secondary structure. Longer binding sites generally were predicted to be segmented, in agreement with available experimentally characterized examples. Scanning several hundred proteomes showed that the occurrence of disordered binding sites increased with the complexity of the organisms even compared to disordered regions in general. Furthermore, the length distribution of binding sites was different from disordered protein regions in general and was dominated by shorter segments. These results underline the importance of disordered proteins and protein segments in establishing new binding regions. Due to their specific biophysical properties, disordered binding sites generally carry a robust sequence signal, and this signal is efficiently captured by our method. Through its generality, ANCHOR opens new ways to study the essential functional sites of disordered proteins.

Dataset Information

Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores.

Publications

Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores.

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