Protein sequence entropy is closely related to packing density and hydrophobicity

Liao, Hong-Yuan Mark; Yeh, William W.‐G.; Chiang, Derek Y.; Jernigan, Robert L.; Lustig, Brooke

doi:10.1093/protein/gzi009

Cited by 71 publications

(84 citation statements)

References 54 publications

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“…It was previously observed that this measurement is directly related to the structure of the protein [30]. Regions with higher sequence entropy (i.e.…”

Section: Epitopes Are Found Adjacent To Variable Sequencesmentioning

confidence: 92%

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

2008

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The development of an effective vaccine against HIV/AIDS has been hampered, in part, by a poor understanding of the rules governing helper T-cell epitope immunodominance. Studies in mice have shown that antigen structure modulates epitope immunodominance by affecting the processing and subsequent presentation of helper T-cell epitopes. Previous epitope mapping studies showed that the immunodominant helper T-cell epitopes in mice immunized with gp120 were found flanking flexible loops of the protein. In this report, we show that helper T-cell epitopes against gp120 in humans infected with HIV are also found flanking flexible loops. Immunodominant epitopes were found to be located primarily in the outer domain, an average of 12 residues C-terminal to flexible loops. In the less immunogenic inner domain, epitopes were found an average of five residues N-terminal to conserved regions of the protein, once again placing the epitopes C-terminal to flexible loops. These results show that antigen structure plays a significant role in the shaping of the helper T-cell response against HIV gp120 in humans. This relationship between antigen structure and helper T-cell epitope immunodominance may prove to be useful in the development of rationally designed vaccines against pathogens such as HIV.Key words: Antigen processing Á Helper T lymphocyte Á HIV envelope protein gp120 Á MHC class II Á Protein structure IntroductionOver the past 25 years, great strides have been made in the area of HIV/AIDS research. Much is now known about the biology and pathogenesis of the virus. In spite of this, HIV/AIDS continues to be a major health problem worldwide. In 2006, there were approximately 4.3 million new HIV cases, 400 000 more cases than in 2004, bringing the global total of people living with HIV to 39.5 million [1]. This number reflects the increase of HIV cases in every region of the world, suggesting that the epidemic is far from declining. In order to reverse this trend, an effective vaccine against HIV must be developed.Studies in humans and non-human primates have shown that the CD8 + cytotoxic T lymphocyte (CTL) response is essential to the control of viremia [2][3][4][5][6]. Neutralizing antibody has also been shown to aid in the maintenance of low viral loads, presumably through the prevention of viral transmission from cell to cell [7][8][9]. CD4 + helper T cells are required for the induction and maintenance of both of these effector mechanisms [10][11][12][13][14][15][16][17][18]. Therefore, the ideal vaccine against HIV must be able to activate these three arms of the immune response in order to confer protection against infection and disease progression. Helper T-cell activation begins when an immature CD4 + T cell encounters an antigen-presenting cell (APC) displaying a peptide bound to an MHC class II molecule (pMHCII). This contact between the CD4 + T cell and the pMHCII complex initiates a signaling cascade that leads to the maturation of the helper T cell. Although every sequence within a protein antigen can poten...

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“…It was previously observed that this measurement is directly related to the structure of the protein [30]. Regions with higher sequence entropy (i.e.…”

Section: Epitopes Are Found Adjacent To Variable Sequencesmentioning

confidence: 92%

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

2008

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“…It has been confirmed that evolutionarily conserved residues in a protein are responsible for its function, stability and/or structural formation [30][31][32][33][34][35]. In this study, we attempt to identify conserved hydrophobic residues.…”

Section: Evolutionary Analysismentioning

confidence: 98%

Properties of Amino Acid Sequences of Lysozyme-Like Superfamily Proteins Relating to Their Folding Mechanisms

Nakashima¹,

Kabata²,

Kikuchi³

2017

J Proteomics Bioinform

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“…protein-protein interaction ͉ hot spots in the interface ͉ residue conservation ͉ crystal packing ͉ quaternary structure prediction E volutionary conservation of amino acid residues may include active-site residues pertaining to the function of the molecule or tightly packed sites contributing to the stable core or indicative of the folding nucleus (1)(2)(3)(4). For cellular function proteins need to interact with other molecules, and techniques such as the twohybrid system and affinity purifications are being used to discover the physical association between proteins, leading to a fascinating view of cell-interaction maps (5,6).…”

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confidence: 99%

Conservation and relative importance of residues across protein-protein interfaces

Guharoy

Chakrabarti

2005

Proc. Natl. Acad. Sci. U.S.A.

244

205

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A core region surrounded by a rim characterizes biological interfaces. We ascertain the importance of the core by showing the sequence entropies of the residues comprising the core to be smaller than those in the rim. Such a distinction is not seen in the 2-fold-related, nonphysiological interfaces formed in crystal lattices of monomeric proteins, thereby providing a procedure for characterizing the oligomeric state from crystal structures of protein molecules. This method is better than those that rely on the comparison of the sequence entropies in the interface and the rest of the protein surface, especially in cases where the surface harbors additional binding sites. To a good approximation there is a correlation between the accessible surface area lost because of complexation and ⌬⌬G values obtained through alanine-scanning mutagenesis (26 -38 cal per Å 2 of the surface buried) for residues located in the core, a relationship that is not discernable for rim residues. If, however, a residue participates in hydrogen bonding across the interface, the extent of stabilization is 52 cal͞mol per 1 Å 2 of the nonpolar surface area buried by the residue. As opposed to an amino acid classification used earlier, an environment-based grouping of residues yields a better discrimination in the sequence entropy between the core and the rim.protein-protein interaction ͉ hot spots in the interface ͉ residue conservation ͉ crystal packing ͉ quaternary structure prediction

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Protein sequence entropy is closely related to packing density and hydrophobicity

Cited by 71 publications

References 54 publications

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

Properties of Amino Acid Sequences of Lysozyme-Like Superfamily Proteins Relating to Their Folding Mechanisms

Conservation and relative importance of residues across protein-protein interfaces

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