Scott Classen: December 2016 Archives

Apoptosis-inducing factor (AIF) is critical for mitochondrial respiratory complex biogenesis and for mediating necroptotic parthanatos; these functions are seemingly regulated by enigmatic allosteric switching driven by NADH charge-transfer complex (CTC) formation. In this paper the authors define molecular pathways linking AIF’s active site to allosteric switching regions by characterizing dimer-permissive mutants using small-angle X-ray scattering (SAXS) and crystallography and by probing AIF-CTC communication networks using molecular dynamics simulations. Collective results identify two pathways propagating allostery from the CTC active site: (1) active-site H454 links to S480 of AIF’s central β-strand to modulate a hydrophobic border at the dimerization interface, and (2) an interaction network links AIF’s FAD cofactor, central β-strand, and Cβ-clasp whereby R529 reorientation initiates C-loop release during CTC formation. This knowledge of AIF allostery and its flavoswitch mechanism provides a foundation for biologically understanding and biomedically controlling its participation in mitochondrial homeostasis and cell death.

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Brosey CA, Ho C, Long WZ, Singh S, Burnett K, Hura GL, Nix JC, Bowman GR, Ellenberger T, Tainer JA. “Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor.” Structure 2016 Dec 06 ;24(12)

Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) repeats. These repeats are structurally similar, but not identical in sequence, often featuring linkers with conserved calcium-binding sites that confer mechanical strength to them. In a paper recently published in Nature Communications the Sotomayor lab reports the X-ray crystal structures of human protocadherin-15 EC8-EC10 and mouse EC9-EC10, which show an EC8-9 canonical-like calcium-binding linker, and an EC9-10 calcium-free linker that alters the linear arrangement of EC repeats. Molecular dynamics simulations and small-angle X-ray scattering experiments support this non-linear conformation. Simulations also suggest that unbending of EC9-10 confers some elasticity to otherwise rigid tip links. The new structure provides a first view of protocadherin-15’s non- canonical EC linkers and suggests how they may function in inner-ear mechanotransduction, with implications for other cadherins.

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Araya-Secchi R, Neel BL, Sotomayor M. “An elastic element in the protocadherin-15 tip link of the inner ear.” Nat Commun 2016 Nov 18 ;7

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