Structure-Function Relationships in Side Chain Lactam Cross-Linked Peptide Models of a Conserved N-Terminal Domain of Apolipoprotein E
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- 作者：Tammie L. S. Benzinger ; Demetrios T. Braddock ; Samuel R. Dominguez ; Timothy S. Burkoth ; Hé ; lè ; ne Miller-Auer ; Ram M. Subramanian ; Gunther M. Fless ; David N. M. Jones ; David G. Lynn ; and St
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：September 22, 1998
- 年：1998
- 卷：37
- 期：38
- 页码：13222 - 13229
- 全文大小：196K
- 年卷期：v.37,no.38(September 22, 1998)
- ISSN：1520-4995
文摘
Bioactive peptides have multiple conformations in solution but adopt well-defined conformationsat lipid surfaces and in interactions with receptors. We have used side chain lactam cross-links to stabilizesecondary structures in the following peptide models of a conserved N-terminal domain of apolipoproteinE (cross-link periodicity in parentheses): I, H2N-GQTLSEQVQEELLSSQVTQELRAG-COOH (none);III, H2N-GDTL KEQVQEELLSEQV KDEL KAG-COOH (i to i + 3); IV, H2N-GQDLSE KVQEELLESQV KDELL KAG-COOH (i to i + 4); IVa, H2N-GQDLSE KVQEELLSEQV KDELL KAG-COOH (i to i + 4)(lactams above the sequence, potential salt bridges below the sequence). We previously demonstrated[Luo et al. (1994) Biochemistry 33, 12367-12377; Braddock et al. (1996) Biochemistry 35, 13975-13984] that peptide III, containing lactam cross-links between the i and i + 3 side chains, enhancesspecific binding of LDL via a receptor other than the LDL-receptor. Peptide III in solution consists oftwo short 
helices connected by a non helical segment. Here we examine the hypothesis that thedomain modeled by peptide III is one antipode of a conformational switch. To model another antipodeof the switch, we introduced two strategic modifications into peptide III to examine structure-functionrelationships in this domain: (1) the spacing of the lactam cross-links was changed (i to i + 4 in peptidesIV and IVa) and (2) peptides IV and IVa contain the two alternative sequences at a site of a possibleend-capping interaction in peptide III. The structure of peptide IV, determined by 2D-NMR, is helicalacross its entire length. Despite the remarkable degree of structural order, peptide IV is biologicallyinactive. In contrast, peptides III and possibly IVa contain a central interruption of the helix, whichappears necessary for biological activity. These and other studies support the hypothesis that this domainis a conformational switch which, to the extent that it models apolipoprotein E itself, may modulateinteractions between apo E and its various receptors.
helices connected by a non helical segment. Here we examine the hypothesis that thedomain modeled by peptide III is one antipode of a conformational switch. To model another antipodeof the switch, we introduced two strategic modifications into peptide III to examine structure-functionrelationships in this domain: (1) the spacing of the lactam cross-links was changed (i to i + 4 in peptidesIV and IVa) and (2) peptides IV and IVa contain the two alternative sequences at a site of a possibleend-capping interaction in peptide III. The structure of peptide IV, determined by 2D-NMR, is helicalacross its entire length. Despite the remarkable degree of structural order, peptide IV is biologicallyinactive. In contrast, peptides III and possibly IVa contain a central interruption of the helix, whichappears necessary for biological activity. These and other studies support the hypothesis that this domainis a conformational switch which, to the extent that it models apolipoprotein E itself, may modulateinteractions between apo E and its various receptors.