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Structural Evidence...
Structural Evidence for an Octameric Ring Arrangement of SARM1
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- Sporny, Michael (författare)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel.
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- Guez-Haddad, Julia (författare)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel.
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- Lebendiker, Mario (författare)
- Hebrew Univ Jerusalem, Wolfson Ctr Appl Struct Biol, Jerusalem, Israel.
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- Ulisse, Valeria (författare)
- Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.
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- Volf, Allison (författare)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel.
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- Mim, Carsten (författare)
- KTH,Strukturell bioteknik,Karolinska Inst, Dept Nutr & Biosci, Huddinge, Sweden.
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- Isupov, Michail N. (författare)
- Univ Exeter, Biosci, Exeter, Devon, England.
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- Opatowsky, Yarden (författare)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel.
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Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290002 Ramat Gan, Israel Hebrew Univ Jerusalem, Wolfson Ctr Appl Struct Biol, Jerusalem, Israel. (creator_code:org_t)
- ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2019
- 2019
- Engelska.
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Ingår i: Journal of Molecular Biology. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 0022-2836 .- 1089-8638. ; 431:19, s. 3591-3605
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- SARM1 induces axonal degeneration in response to various insults and is therefore considered an attractive drug target for the treatment of neuro-degenerative diseases as well as for brain and spinal cord injuries. SARM1 activity depends on the integrity of the protein's SAM domains, as well as on the enzymatic conversion of NAD + to ADPR (ADP Ribose) products by the SARM1's TIR domain. Therefore, inhibition of either SAM or TIR functions may constitute an effective therapeutic strategy. However, there is currently no SARM1-directed therapeutic approach available because of an insufficient structural and mechanistic understanding of this protein. In this study, we found that SARM1 assembles into an octameric ring. This arrangement was not described before in other SAM proteins, but is reminiscent of the apoptosome and inflammasome well-known apoptotic ring-like oligomers. We show that both SARM1 and the isolated tandem SAM(1-2) domains form octamers in solution, and electron microscopy analysis reveals an octameric ring of SARM1. We determined the crystal structure of SAM(1-2) and found that it also forms a closed octameric ring in the crystal lattice. The SAM(1-2) ring interactions are mediated by complementing "lock and key" hydrophobic grooves and inserts and electrostatic charges between the neighboring protomers. We have mutated several interacting SAM1-2 interfaces and measured how these mutations affect SARM1 apoptotic activity in cultured cells, and in this way identified critical oligomerization sites that facilitate cell death. These results highlight the importance of oligomerization for SARM1 function and reveal critical epitopes for future targeted drug development. Elsevier Ltd. All rights reserved.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- SARM1
- SAM domain
- cell death
- x-ray crystallography
- electron microscopy
- Bioteknologi
- Biotechnology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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