4CI8

Crystal structure of the tandem atypical beta-propeller domain of EML1

4CI8 の概要

• エントリーDOI: 10.2210/pdb4ci8/pdb
• 分子名称: ECHINODERM MICROTUBULE-ASSOCIATED PROTEIN-LIKE 1, SULFATE ION (3 entities in total)
• 機能のキーワード: structural protein, eml1, eml4-alk, hsp90 inhibitors, tubulin-binding, beta propeller
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm : O00423
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 147778.89

構造登録者

Richards, M.W.,Bayliss, R. (登録日: 2013-12-06, 公開日: 2014-04-16, 最終更新日: 2024-05-08)

主引用文献

Richards, M.W.,Law, E.W.P.,Rennalls, L.P.,Busacca, S.,O'Regan, L.,Fry, A.M.,Fennell, D.A.,Bayliss, R.
Crystal Structure of Eml1 Reveals the Basis for Hsp90 Dependence of Oncogenic Eml4-Alk by Disruption of an Atypical Beta-Propeller Domain.
Proc.Natl.Acad.Sci.USA, 111:5195-, 2014

PubMed Abstract: Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners.

PubMed: 24706829
DOI: 10.1073/PNAS.1322892111

実験手法

X-RAY DIFFRACTION (2.6 Å)