Primary and secondary dimer interfaces of the fibroblast growth factor receptor 3 transmembrane domain: characterization via multiscale molecular dynamics simulations.

Authors:
Tyler Reddy
Tyler Reddy
Dalhousie University
Canada
Santiago Manrique
Santiago Manrique
Department of Biology-University Roma Tre
Italy
Amanda Buyan
Amanda Buyan
University of Wisconsin
United States
Benjamin A Hall
Benjamin A Hall
University of Oxford
United Kingdom
Alan Chetwynd
Alan Chetwynd
University of Oxford
United Kingdom

Biochemistry 2014 Jan 8;53(2):323-32. Epub 2014 Jan 8.

Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.

Receptor tyrosine kinases are single-pass membrane proteins that form dimers within the membrane. The interactions of their transmembrane domains (TMDs) play a key role in dimerization and signaling. Fibroblast growth factor receptor 3 (FGFR3) is of interest as a G380R mutation in its TMD is the underlying cause of ~99% of the cases of achondroplasia, the most common form of human dwarfism. The structural consequences of this mutation remain uncertain: the mutation shifts the position of the TMD relative to the lipid bilayer but does not alter the association free energy. We have combined coarse-grained and all-atom molecular dynamics simulations to study the dimerization of wild-type, heterodimer, and mutant FGFR3 TMDs. The simulations reveal that the helices pack together in the dimer to form a flexible interface. The primary packing mode is mediated by a Gx3G motif. There is also a secondary dimer interface that is more highly populated in heterodimer and mutant configurations that may feature in the molecular mechanism of pathology. Both coarse-grained and atomistic simulations reveal a significant shift of the G380R mutant dimer TMD relative to the bilayer to allow interactions of the arginine side chain with lipid headgroup phosphates.

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Source
http://pubs.acs.org/doi/10.1021/bi401576k
Publisher Site
http://dx.doi.org/10.1021/bi401576kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871223PMC

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January 2014
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