5tvb
Structure of the TPR oligomerization domain
Structural highlights
DiseaseTPR_HUMAN Papillary or follicular thyroid carcinoma. A chromosomal aberration involving TPR has been found in papillary thyroid carcinomas (PTCs). Intrachromosomal rearrangement that links the 5'-end of the TPR gene to the protein kinase domain of NTRK1 forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the carboxy terminus of the NTRK1 protein.[1] Involved in tumorigenic rearrangements with the MET.[2] FunctionTPR_HUMAN Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with NUP153, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Negatively regulates both the association of CTE-containing mRNA with large polyribosomes and translation initiation. Does not play any role in Rev response element (RRE)-mediated export of unspliced mRNAs. Implicated in nuclear export of mRNAs transcribed from heat shock gene promoters; associates both with chromatin in the HSP70 promoter and with mRNAs transcribed from this promoter under stress-induced conditions. Modulates the nucleocytoplasmic transport of activated MAPK1/ERK2 and huntingtin/HTT and may serve as a docking site for the XPO1/CRM1-mediated nuclear export complex. According to some authors, plays a limited role in the regulation of nuclear protein export (PubMed:22253824 and PubMed:11952838). Plays also a role as a structural and functional element of the perinuclear chromatin distribution; involved in the formation and/or maintenance of NPC-associated perinuclear heterochromatin exclusion zones (HEZs). Finally, acts as a spatial regulator of the spindle-assembly checkpoint (SAC) response ensuring a timely and effective recruitment of spindle checkpoint proteins like MAD1L1 and MAD2L1 to unattached kinetochore during the metaphase-anaphase transition before chromosome congression. Its N-terminus is involved in activation of oncogenic kinases.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Publication Abstract from PubMedThe nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2-142), the MET fusion partner of oncogenic TPR-MET. TPR(2-142) contains a continuous 124-residue alpha helix that forms an antiparallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature. We further show that fusion of TPR(2-142) to the MET intracellular domain strongly and selectively stabilizes the alphaG helix of the MET kinase domain, and mutations of only the TPR leucine zipper residues at the junction to MET, but not other leucine zipper residues, abolish kinase activation. Together, these results provide critical insight into the TPR structure and its ability to induce dimerization and activation of fusion kinases. Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases.,Pal K, Bandyopadhyay A, Zhou XE, Xu Q, Marciano DP, Brunzelle JS, Yerrum S, Griffin PR, Vande Woude G, Melcher K, Xu HE Structure. 2017 Jun 6;25(6):867-877.e3. doi: 10.1016/j.str.2017.04.015. Epub 2017, May 18. PMID:28528776[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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