9E7C

TRK-fused Gene (TFG) PB1 Domain D60A/D62R Variant

Summary for 9E7C

• Entry DOI: 10.2210/pdb9e7c/pdb
• Descriptor: Protein TFG (2 entities in total)
• Functional Keywords: type i/ii pb1 domain, octamer, ubiquitin like beta-grasp fold, globular, protein transport
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 11404.23

Authors

Schuh, A.L.,Bhattacharyya, B.,Keck, J.L.,Audhya, A. (deposition date: 2024-11-01, release date: 2024-11-20, Last modification date: 2024-12-04)

Primary citation

Zhang, Z.,Lettman, M.M.,Schuh, A.L.,Bhattacharyya, B.,Randolph, P.,Nandakumar, T.,Kulkarni, I.,Roach, A.,Alvin, J.R.,Gengler, D.,Stagg, S.M.,Keck, J.L.,Audhya, A.
Multiple roles for TFG ring complexes in neuronal cargo trafficking.
Biorxiv, 2024

PubMed Abstract: Pathological variants in Trk-fused gene (TFG) have been implicated in a variety of neurodegenerative conditions. In particular, mutations within its amino-terminal PB1 domain have been suggested to cause hereditary spastic paraplegia (HSP), resulting in progressive lower limb spasticity and weakness. The structural basis for this effect is unknown. Here, we combine X-ray crystallography and cryo-electron microscopy to determine a structural model of TFG, demonstrating the mechanism by which it forms octameric ring complexes. A network of electrostatic and hydrophobic interactions defines the interface between protomers. Moreover, we show that mutations identified previously in HSP patients disrupt this interface, destabilizing octamers, which ultimately leads to axonopathy. Surprisingly, the impacts of these variants are not equivalent in vivo, highlighting the existence of multiple, distinct mechanisms by which TFG mutations contribute to neurodegenerative disease.

PubMed: 39574627
DOI: 10.1101/2024.11.05.621662

Experimental method

X-RAY DIFFRACTION (1.906 Å)