Structure-based mechanism of preferential complex formation by apoptosis signal–regulating kinases

• DOI: 10.1126/scisignal.aay6318
• Publication Date: 2020-03-10T23:15:27Z
• Authors: Sarah J. Trevelyan; Jodi L. Brewster; Abigail E. Burgess; Jennifer M. Crowther; Antonia L. Cadell; Benjamin L. Parker; David R. Croucher; Renwick C. J. Dobson; James M. Murphy; Peter D. Mace
• Keywords: 0303 health sciences; 03 medical and health sciences; HEK293 Cells; Protein Domains; Multienzyme Complexes; Humans; Protein Multimerization; MAP Kinase Kinase Kinase 5; MAP Kinase Kinase Kinases

Apoptosis signal-regulating kinases (ASK1, ASK2, and ASK3) are activators of the p38 c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAPK) pathways. ASK1-3 form oligomeric complexes known as ASK signalosomes that initiate signaling cascades in response to diverse stress stimuli. Here, we demonstrated oligomerization proteins is driven by previously uncharacterized sterile-alpha motif (SAM) domains reside at carboxy-terminus each protein. SAM from exhibited distinct behaviors, with domain ASK1 forming unstable oligomers, ASK2 remaining predominantly monomeric, ASK3 a stable oligomer even low concentration. In contrast their behavior isolation, preferentially formed heterocomplex. The crystal structure domain, small-angle x-ray scattering, mutagenesis suggested oligomers ASK1-ASK2 discrete, quasi-helical rings through interactions between mid-loop one molecule end helix another molecule. Preferential binding was consistent mass spectrometry showing full-length hetero-oligomeric incorporating large amounts ASK2. Accordingly, disrupting association impaired activity context electrophilic induced 4-hydroxy-2-nonenal (HNE). These findings provide structural template for how assemble foci drive inflammatory reinforce notion strategies target should consider concerted actions multiple family members.