7YWD

Human GDAP1 core domain, trigonal crystal form

7YWD の概要

• エントリーDOI: 10.2210/pdb7ywd/pdb
• 関連するPDBエントリー: 7Q6J 7Q6K
• 分子名称: Ganglioside-induced differentiation-associated protein 1 (1 entity in total)
• 機能のキーワード: gst homology, mitochondrial outer membrane, charcot-marie-tooth disease, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 127529.65

構造登録者

Raasakka, A.,Kursula, P. (登録日: 2022-02-13, 公開日: 2022-06-08, 最終更新日: 2024-11-13)

主引用文献

Sutinen, A.,Nguyen, G.T.T.,Raasakka, A.,Muruganandam, G.,Loris, R.,Ylikallio, E.,Tyynismaa, H.,Bartesaghi, L.,Ruskamo, S.,Kursula, P.
Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1.
Febs Open Bio, 12:1306-1324, 2022

PubMed Abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R and CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behavior, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side-chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and, eventually, insufficient motor and sensory neuron function.

PubMed: 35509130
DOI: 10.1002/2211-5463.13422

実験手法

X-RAY DIFFRACTION (3.2 Å)