4.2 Article

Structure determination of human Fas apoptosis inhibitory molecule and identification of the critical residues linking the interdomain interaction to the anti-apoptotic activity

Journal

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
Volume 70, Issue -, Pages 1812-1822

Publisher

INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S1399004714004854

Keywords

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Funding

  1. NSFC [30930020]
  2. National High Technology and Development Program of China 973 program [2010CB911800]
  3. International Centre for Genetic Engineering and Biotechnology (ICGEB) [CRP/CHN09-01]
  4. 863 program [2006AA02A323]

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Fas apoptosis inhibitory molecule (FAIM) is a highly conserved anti-apoptotic protein which plays important roles in cells. There are two isoforms of FAIM, of which the short isoform FAIM-S is broadly expressed in all tissues, whereas the long isoform FAIM-L is exclusively expressed in the nervous system. No structure of human FAIM has been reported to date and the detailed molecular mechanisms underlying the anti-apoptotic function of FAIM remain unknown. Here, the crystal structure of the human FAIM-S N-terminal domain (NTD) and the NMR solution structure of the human FAIM-S C-terminal domain (CTD) were determined. The structures revealed that the NTD and CTD adopt a similar protein fold containing eight antiparallel beta-strands which form two sheets. Both structural and biochemical analyses implied that the NTD exists as a dimer and the CTD as a monomer and that they can interact with each other. Several critical residues were identified to be involved in this interaction. Moreover, mutations of these critical residues also interfered in the anti-apoptotic activity of FAIM-S. Thus, the structural and functional data presented here will provide insight into the anti-apoptotic mechanism of FAIM-S.

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