Solution structures of the inactivation gate particle peptides of rat brain type-IIA and human heart sodium channels in SDS micelles

Citation
K. Miyamoto et al., Solution structures of the inactivation gate particle peptides of rat brain type-IIA and human heart sodium channels in SDS micelles, J PEPT RES, 57(3), 2001, pp. 203-214
Citations number
35
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF PEPTIDE RESEARCH
ISSN journal
1397-002X → ACNP
Volume
57
Issue
3
Year of publication
2001
Pages
203 - 214
Database
ISI
SICI code
1397-002X(200103)57:3<203:SSOTIG>2.0.ZU;2-N
Abstract
The Ile-Phe-Met (IFM) motif located in the Ill-IV linker of voltage-gated s odium channels has been identified as a major component of the fast inactiv ation gate, if Gin was substituted for Phe, the role in the gate was disrup ted completely. If lie was replaced by Gin inactivation became slightly inc omplete and if the Thr, which is adjacent to the IFM motif (-IFMT-), was re placed by Met, inactivation became much more incomplete than in the I/Q mut ation, but not as vigorous as in the F/Q mutation. Previously, we studied t he structures of the inactivation gate-related peptide (K1480-K1496 in rat brain type-IIA, MP-3A) and its F1489/Q substituted one (MP-4A) in SDS micel les and found that the conformational change of the IFM hydrophobic cluster due to the F/Q substitution may be a reason for disrupting the gate. In th is study, in order to obtain supporting evidence for this view and also to further knowledge of the effect of I/Q and T/M mutations on the structure o f the IFM cluster, we studied the structures of 11488Q [MP(rb)-3QFMT] and T 1491M [MP(rb)-3lFMM] substituted peptides. The fragment peptide K1477-K1493 [MP(hh)-3A] and its T1488M substituted peptide [MP(hh)-31FMM] in the human heart sodium channel were also studied. It was found that the backbone str uctures around the IMF motif of MP-3A, MP(hh)-3A and MP(rb)-3QFMT resemble one another in such a manner that the residues Ile(Gln) and Thr are brought so close together that they form a unique type of lid to occlude the pore. In contrast, the residues between lie and M1491 of MP(rb)-31FMM or M1488 o f MP(hh)-31FMM were fairly far apart from each other. We conclude that Thr plays an important role in forming a structure of the IFM hydrophobic clust er for inactivation.