2NZI

Crystal structure of domains A168-A170 from titin

2NZI の概要

• エントリーDOI: 10.2210/pdb2nzi/pdb
• 分子名称: Titin (2 entities in total)
• 機能のキーワード: ig-domain, fniii-domain, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm (Probable): Q8WZ42
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67840.72

構造登録者

Mrosek, M.C.,Labeit, D.,Labeit, S.,Mayans, O. (登録日: 2006-11-23, 公開日: 2007-02-13, 最終更新日: 2023-12-27)

主引用文献

Mrosek, M.,Labeit, D.,Witt, S.,Heerklotz, H.,von Castelmur, E.,Labeit, S.,Mayans, O.
Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin.
Faseb J., 21:1383-1392, 2007

PubMed Abstract: Titin forms an intrasarcomeric filament system in vertebrate striated muscle, which has elastic and signaling properties and is thereby central to mechanotransduction. Near its C-terminus and directly preceding a kinase domain, titin contains a conserved pattern of Ig and FnIII modules (Ig(A168)-Ig(A169)-FnIII(A170), hereby A168-A170) that recruits the E3 ubiquitin-ligase MuRF-1 to the filament. This interaction is thought to regulate myofibril turnover and the trophic state of muscle. We have elucidated the crystal structure of A168-A170, characterized MuRF-1 variants by circular dichroism (CD) and SEC-MALS, and studied the interaction of both components by isothermal calorimetry, SPOTS blots, and pull-down assays. This has led to the identification of the molecular determinants of the binding. A168-A170 shows an extended, rigid architecture, which is characterized by a shallow surface groove that spans its full length and a distinct loop protrusion in its middle point. In MuRF-1, a C-terminal helical domain is sufficient to bind A168-A170 with high affinity. This helical region predictably docks into the surface groove of A168-A170. Furthermore, pull-down assays demonstrate that the loop protrusion in A168-A170 is a key mediator of MuRF-1 recognition. Our findings indicate that this region of titin could serve as a target to attempt therapeutic inhibition of MuRF-1-mediated muscle turnover, where binding of small molecules to its distinctive structural features could block MuRF-1 access.

PubMed: 17215480
DOI: 10.1096/fj.06-7644com

実験手法

X-RAY DIFFRACTION (2.9 Å)