5TO5

Structure of the TPR oligomerization domain

Summary for 5TO5

• Entry DOI: 10.2210/pdb5to5/pdb
• Related: 5TO6 5TO7
• Descriptor: Nucleoprotein TPR (2 entities in total)
• Functional Keywords: tpr oligomerization domain, receptor tyrosine kinase, met, oncogenic fusion kinases, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 33495.84

Authors

Pal, K.,Xu, Q.,Zhou, X.E.,Melcher, K.,Xu, H.E. (deposition date: 2016-10-16, release date: 2017-10-18, Last modification date: 2024-03-06)

Primary citation

Pal, K.,Bandyopadhyay, A.,Zhou, X.E.,Xu, Q.,Marciano, D.P.,Brunzelle, J.S.,Yerrum, S.,Griffin, P.R.,Vande Woude, G.,Melcher, K.,Xu, H.E.
Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases.
Structure, 25:867-877.e3, 2017

PubMed Abstract: The 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 α 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 αG 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.

PubMed: 28528776
DOI: 10.1016/j.str.2017.04.015

Experimental method

X-RAY DIFFRACTION (2.5 Å)