title: FGFR3 unliganded dimer stabilization by the juxtamembrane domain.
abstract: Receptor tyrosine kinases (RTKs) conduct biochemical signals upon dimerization in the membrane plane. While RTKs are generally known to be activated in response to ligand binding, many of these receptors are capable of forming unliganded dimers that are likely important intermediates in the signaling process. All 58 RTKs consist of an extracellular (EC) domain, a transmembrane (TM) domain, and an intracellular domain that includes a juxtamembrane (JM) sequence and a kinase domain. Here we investigate directly the effect of the JM domain on unliganded dimer stability of FGFR3, a receptor that is critically important for skeletal development. The data suggest that FGFR3 unliganded dimers are stabilized by receptor-receptor contacts that involve the JM domains. The contribution is significant, as it is similar in magnitude to the stabilizing contribution of a pathogenic mutation and the repulsive contribution of the EC domain. Furthermore, we show that the effects of the JM domain and a TM pathogenic mutation on unliganded FGFR3 dimer stability are additive. We observe that the JM-mediated dimer stabilization occurs when the JM domain is linked to FGFR3 TM domain and not simply anchored to the plasma membrane. These results point to a coordinated stabilization of the unliganded dimeric state of FGFR3 by its JM and TM domains via a mechanism that is distinctly different from the case of another well studied receptor, EGFR.
authors: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, USA.
authors: Sarvenaz
authors: S
authors: Sarabipour
authors: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, USA. Electronic address: kh@jhu.edu.
authors: Kalina
authors: K
authors: Hristova
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D021382:Protein Sorting Signals; D055550:Protein Stability; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry* / Q000235:genetics; D013816:Thermodynamics
chemical_list: D021382:Protein Sorting Signals; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: juxtamembrane domain; membrane protein dimerization; receptor tyrosine kinases; thermodynamics; transmembrane domain