6QWV

SARM1 SAM1-2 domains

6QWV の概要

• エントリーDOI: 10.2210/pdb6qwv/pdb
• 分子名称: Sterile alpha and TIR motif-containing protein 1, 1,2-ETHANEDIOL, BETA-MERCAPTOETHANOL, ... (6 entities in total)
• 機能のキーワード: ----, apoptosis
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 305925.37

構造登録者

Sporny, M.,Isupov, N.M.,Opatowsky, Y. (登録日: 2019-03-06, 公開日: 2019-07-03, 最終更新日: 2019-09-18)

主引用文献

Sporny, M.,Guez-Haddad, J.,Lebendiker, M.,Ulisse, V.,Volf, A.,Mim, C.,Isupov, M.N.,Opatowsky, Y.
Structural Evidence for an Octameric Ring Arrangement of SARM1.
J.Mol.Biol., 431:3591-3605, 2019

PubMed Abstract: SARM1 induces axonal degeneration in response to various insults and is therefore considered an attractive drug target for the treatment of neuro-degenerative diseases as well as for brain and spinal cord injuries. SARM1 activity depends on the integrity of the protein's SAM domains, as well as on the enzymatic conversion of NAD+ to ADPR (ADP Ribose) products by the SARM1's TIR domain. Therefore, inhibition of either SAM or TIR functions may constitute an effective therapeutic strategy. However, there is currently no SARM1-directed therapeutic approach available because of an insufficient structural and mechanistic understanding of this protein. In this study, we found that SARM1 assembles into an octameric ring. This arrangement was not described before in other SAM proteins, but is reminiscent of the apoptosome and inflammasome-well-known apoptotic ring-like oligomers. We show that both SARM1 and the isolated tandem SAM domains form octamers in solution, and electron microscopy analysis reveals an octameric ring of SARM1. We determined the crystal structure of SAM and found that it also forms a closed octameric ring in the crystal lattice. The SAM ring interactions are mediated by complementing "lock and key" hydrophobic grooves and inserts and electrostatic charges between the neighboring protomers. We have mutated several interacting SAM interfaces and measured how these mutations affect SARM1 apoptotic activity in cultured cells, and in this way identified critical oligomerization sites that facilitate cell death. These results highlight the importance of oligomerization for SARM1 function and reveal critical epitopes for future targeted drug development.

PubMed: 31278906
DOI: 10.1016/j.jmb.2019.06.030

実験手法

X-RAY DIFFRACTION (2.47 Å)