PDBsum entry 4ci8

Structural protein

PDB id: 4ci8

Contents

Protein chains

640 a.a.

Ligands

SO4 ×25

Waters ×208

PDB id:

4ci8

Name:

Structural protein

Title:

Crystal structure of the tandem atypical beta-propeller domain of eml1

Structure:

Echinoderm microtubule-associated protein-like 1. Chain: a, b. Fragment: residues 167-815. Synonym: emap-1, huemap-1 protein 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.60Å R-factor: 0.202 R-free: 0.251

Authors:

M.W.Richards,R.Bayliss

Key ref:

M.W.Richards et al. (2014). Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc Natl Acad Sci U S A, 111, 5195-5200. PubMed id: 24706829 DOI: 10.1073/pnas.1322892111

Date:

06-Dec-13 Release date: 16-Apr-14

Protein chains

O00423  (EMAL1_HUMAN) -  Echinoderm microtubule-associated protein-like 1 from Homo sapiens

Seq: 815 a.a.

Struc: 640 a.a.

DOI no: 10.1073/pnas.1322892111

Proc Natl Acad Sci U S A 111:5195-5200 (2014)

PubMed id: 24706829

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain.

M.W.Richards, E.W.Law, L.P.Rennalls, S.Busacca, L.O'Regan, A.M.Fry, D.A.Fennell, R.Bayliss.

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.