2mfq | pdb_00002mfq
NMR solution structures of FRS2a PTB domain with neurotrophin receptor TrkB
Structural highlights
Disease[NTRK2_HUMAN] Defects in NTRK2 are the cause of obesity hyperphagia and developmental delay (OHPDD) [MIM:613886]. OHPDD is a disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language.[1] Function[FRS2_HUMAN] Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1.[2] [3] [NTRK2_HUMAN] Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia.[4] Publication Abstract from PubMedThe fibroblast growth factor substrate 2 (FRS2) family proteins function as scaffolding adapters for receptor tyrosine kinases (RTKs). The FRS2alpha proteins interact with RTKs through the phosphotyrosine-binding domain (PTB) and transfer signals from the activated receptors to downstream effector proteins. Here, we report the NMR structure of the FRS2alpha PTB domain bound to phosphorylated TrkB. The structure reveals that the FRS2alpha-PTB domain is comprised of two distinct but adjacent pockets for its mutually exclusive interaction with either non-phosphorylated juxtamembrane region of the FGFR, or tyrosine phosphorylated peptides TrkA and TrkB. The new structural insights suggest rational design of selective small molecules through targeting of the two conjunct pockets in the FRS2alpha PTB domain. (c) Proteins 2014;. (c) 2014 Wiley Periodicals, Inc. Structural insights into FRS2alpha PTB domain recognition by neurotrophin receptor TrkB.,Zeng L, Kuti M, Mujtaba S, Zhou MM Proteins. 2014 Jan 27. doi: 10.1002/prot.24523. PMID:24470253[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||||
