6AMB

Crystal Structure of the Afadin RA1 domain in complex with HRAS

6AMB の概要

• エントリーDOI: 10.2210/pdb6amb/pdb
• 分子名称: GTPase HRas, Afadin, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: gtpase, adhesion, ra domain, rbd domain, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane. Isoform 2: Nucleus: P01112; Cell junction, adherens junction: Q9QZQ1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31462.41

構造登録者

Smith, M.J.,Ishiyama, N.,Ikura, M. (登録日: 2017-08-09, 公開日: 2017-11-01, 最終更新日: 2023-10-04)

主引用文献

Smith, M.J.,Ottoni, E.,Ishiyama, N.,Goudreault, M.,Haman, A.,Meyer, C.,Tucholska, M.,Gasmi-Seabrook, G.,Menezes, S.,Laister, R.C.,Minden, M.D.,Marschalek, R.,Gingras, A.C.,Hoang, T.,Ikura, M.
Evolution of AF6-RAS association and its implications in mixed-lineage leukemia.
Nat Commun, 8:1099-1099, 2017

PubMed Abstract: Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding of MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements.

PubMed: 29062045
DOI: 10.1038/s41467-017-01326-5

実験手法

X-RAY DIFFRACTION (2.5 Å)