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Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
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Number of Authors: 82019 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 5, no 7, article id eaau4202Article in journal (Refereed) Published
Abstract [en]

Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFR alpha 2 and determined its structure at 5.7-angstrom resolution by cryo-EM. The proteins form an assembly through RET-GFR alpha 2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFR alpha 2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.

Place, publisher, year, edition, pages
2019. Vol. 5, no 7, article id eaau4202
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Biological Sciences
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URN: urn:nbn:se:su:diva-171772DOI: 10.1126/sciadv.aau4202ISI: 000478770400007PubMedID: 31392261OAI: oai:DiVA.org:su-171772DiVA, id: diva2:1346518
Available from: 2019-08-28 Created: 2019-08-28 Last updated: 2019-08-28Bibliographically approved

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