NMR studies reveal a novel mode for hFADD to bind with the unstructured hRTN3 which initiates the ER-stress activated apoptosis.
RTN3 can recruit Fas-associated death domain (FADD), thus initiating the ER-stress activated apoptosis. It also interacts with the beta-secretase and its aggregation is critically associated with Alzheimer's disease. Here, we first investigated the solution conformation of hRTN3, subsequently characterized its binding with hFADD. The results reveal: (1) both hRTN3 N- and C-termini are intrinsically unstructured. Nevertheless, the C-terminus contains two short helix-populated regions. (2) The unstructured hRTN3 C-terminus can bind to hFADD as shown by ITC. Further NMR investigation successfully identified the binding involved hRTN3 residues. (3) Although upon hRTN3-binding, the perturbed hFADD residues were distributed over the whole sequence, the majority of the significantly perturbed are over its death effector domain, very different from the previously observed binding mode for FADD. This study also implies a possible linkage between Alzheimer's disease and ER-stress activated apoptosis.
Liu
Jingxian
J
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore.
Zhu
Wanlong
W
Qin
Haina
H
Song
Jianxing
J
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D017209:Apoptosis; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding / Q000235:genetics
D002352:Carrier Proteins; D053200:Fas-Associated Death Domain Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C476198:RTN3 protein, human