6PPM

Ancestral Caspase 6

6PPM の概要

• エントリーDOI: 10.2210/pdb6ppm/pdb
• 関連するPDBエントリー: 6PDQ
• 分子名称: Ancestral Caspase-6 Large Subunit, Ancestral Caspase-6 small subunit, VAL-GLU-ILE-ASP Inhibitor, ... (4 entities in total)
• 機能のキーワード: ancestral effector caspase, protease, ancestral protein reconstruction, apoptosis
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 115588.16

構造登録者

Clark, A.C. (登録日: 2019-07-08, 公開日: 2019-11-13, 最終更新日: 2023-10-11)

主引用文献

Grinshpon, R.D.,Shrestha, S.,Titus-McQuillan, J.,Hamilton, P.T.,Swartz, P.D.,Clark, A.C.
Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity.
Biochem.J., 476:3475-3492, 2019

PubMed Abstract: Apoptotic caspases evolved with metazoans more than 950 million years ago (MYA), and a series of gene duplications resulted in two subfamilies consisting of initiator and effector caspases. The effector caspase genes (caspases-3, -6, and -7) were subsequently fixed into the Chordata phylum more than 650 MYA when the gene for a common ancestor (CA) duplicated, and the three effector caspases have persisted throughout mammalian evolution. All caspases prefer an aspartate residue at the P1 position of substrates, so each caspase evolved discrete cellular roles through changes in substrate recognition at the P4 position combined with allosteric regulation. We examined the evolution of substrate specificity in caspase-6, which prefers valine at the P4 residue, compared with caspases-3 and -7, which prefer aspartate, by reconstructing the CA of effector caspases (AncCP-Ef1) and the CA of caspase-6 (AncCP-6An). We show that AncCP-Ef1 is a promiscuous enzyme with little distinction between Asp, Val, or Leu at P4. The specificity of caspase-6 was defined early in its evolution, where AncCP-6An demonstrates a preference for Val over Asp at P4. Structures of AncCP-Ef1 and of AncCP-6An show a network of charged amino acids near the S4 pocket that, when combined with repositioning a flexible active site loop, resulted in a more hydrophobic binding pocket in AncCP-6An. The ancestral protein reconstructions show that the caspase-hemoglobinase fold has been conserved for over 650 million years and that only three substitutions in the scaffold are necessary to shift substrate selection toward Val over Asp.

PubMed: 31675069
DOI: 10.1042/BCJ20190625

実験手法

X-RAY DIFFRACTION (2.61 Å)