TY - JOUR
T1 - Rational design, solution conformation and identification of functional residues of the soluble and structured Nogo-54, which mimics Nogo-66 in inhibiting the CNS neurite outgrowth
AU - Li, Minfen
AU - Li, Yali
AU - Liao, Xuanhao
AU - Liu, Jingxian
AU - Qin, Haina
AU - Xiao, Zhi-Cheng
AU - Song, Jianxing
PY - 2008
Y1 - 2008
N2 - The interaction between Nogo-66 and its receptor NgR represents a promising target for designing drugs to treat CNS axonal injury which often leads to permanent disability. Unfortunately, the isolated Nogo-66 is highly insoluble while its truncated form Nogo-40 is soluble but unstructured, thus retarding further characterization and application. Here, we rationally design another soluble form Nogo-54. CD and NMR characterization reveals that Nogo-54 is structured, and importantly, is able to mimic Nogo-66 in inhibiting neurite outgrowth. Strikingly, mutating its C-terminal four residues (Lys50, Glu51, Arg53, and Arg54) leads to a mutant Nogo-54m which has no dramatic structural change but whose inhibitory activity is completely abolished. This strongly suggests that the four charged residues contribute significantly to the inhibitory action of Nogo-66. Furthermore, our study also provides a soluble and structured mimic as well as a possible antagonist for Nogo-66 which may hold promising potential for various medical applications.
AB - The interaction between Nogo-66 and its receptor NgR represents a promising target for designing drugs to treat CNS axonal injury which often leads to permanent disability. Unfortunately, the isolated Nogo-66 is highly insoluble while its truncated form Nogo-40 is soluble but unstructured, thus retarding further characterization and application. Here, we rationally design another soluble form Nogo-54. CD and NMR characterization reveals that Nogo-54 is structured, and importantly, is able to mimic Nogo-66 in inhibiting neurite outgrowth. Strikingly, mutating its C-terminal four residues (Lys50, Glu51, Arg53, and Arg54) leads to a mutant Nogo-54m which has no dramatic structural change but whose inhibitory activity is completely abolished. This strongly suggests that the four charged residues contribute significantly to the inhibitory action of Nogo-66. Furthermore, our study also provides a soluble and structured mimic as well as a possible antagonist for Nogo-66 which may hold promising potential for various medical applications.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18585367
U2 - 10.1016/j.bbrc.2008.06.052
DO - 10.1016/j.bbrc.2008.06.052
M3 - Article
VL - 373
SP - 498
EP - 503
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 4
ER -