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. 2019 Sep 16;9:13315. doi: 10.1038/s41598-019-49633-9

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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CED-4 S81 and E88 face away from the CED-3 or CED-9 interaction sites that regulate apoptosis, but might be available to interact with a factor that licenses transient CED-3 activation for localized repair. (a) Ribbon structure shows a CED-4 dimer (most residues in tan, but CARD domain in green with S81 and E88 highlighted in red), with two interacting CED-3 fragment residues (indicated in blue) as determined from a crystal structure. Note that the CARD domain is positioned apart from the CED-3 interaction domain and that S81 and E88 are oriented away from the main structure such that the subdomain that includes S81 and E88 might interact with another protein (or another region of a dynamic CED-4). (b) Ribbon structure shows a partial CED-4 dimer with one CARD domain depicted (CARD domain green, with S81 and E88 in red), binding to the CED-9 protein (magenta). Note that the CARD domain helix 6 containing S81 and E88 is positioned apart from the CED-9 interaction domain, with those AA positions facing outward from the protein. (c) A proposed model of CED-4 non-apoptotic function in neuronal repair shows (i) the two essential amino acids (S81 and E88 shown as yellow dots) in CED-4 helix 6 binding to a hypothetical inhibitor (red, indicated as a protein but could be an ion-binding site associated with conformational change); two green shades of CED-4 represent S and L isoforms. Upon injury (ii), the inhibition might be transiently relieved, enabling CED-4 to locally activate CED-3 caspase. Note that known apoptosis inhibitor CED-9 binds to the opposite side of the CARD helix 6 domain and is unlikely to be directly involved at the helix 6 sites. (iii) The substitution of alanine for S81 and E88 may reduce the affinity of the inhibitor to bind to the CED-4 dimer and subsequently increase the capacity to activate CED-3 in response to injury stress. When S81 and E88 in the CARD domain are absent, the interaction with the inhibitor is weakened and regeneration outgrowth is increased in a CED-3 caspase-dependent mechanism under injury conditions.