6AMB

Crystal Structure of the Afadin RA1 domain in complex with HRAS

Summary for 6AMB

• Entry DOI: 10.2210/pdb6amb/pdb
• Descriptor: GTPase HRas, Afadin, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (5 entities in total)
• Functional Keywords: gtpase, adhesion, ra domain, rbd domain, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane. Isoform 2: Nucleus: P01112; Cell junction, adherens junction: Q9QZQ1
• Total number of polymer chains: 2
• Total formula weight: 31462.41

Authors

Smith, M.J.,Ishiyama, N.,Ikura, M. (deposition date: 2017-08-09, release date: 2017-11-01, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)